Obesity and overweight in R/R DLBCL patients is associated with a better response to treatment of R2-GDP-GOTEL trial. Potential role of NK CD8+cells and vitamin D

Hon ecillas‑P ie oe al. Cance & Me abolism (2025) 13:12
h ps://doi.o g/10.1186/s40170‑025‑00381‑7
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Cance & Me abolism
Obesi y ando e weigh inR/R DLBCL
pa ien s isassocia ed wi habe e esponse
o ea men o R2‑GDP‑GOTEL ial. Po en ial
ole o NK CD8 + cells and i amin D
Lou des Hon ecillas-P ie o1,2,3†, Daniel J. Ga cía-Domínguez2,4†, Ca los Jiménez-Co egana2,
Es eban Nogales-Fe nández3,5, Na alia Palazón-Ca ión3,5, Alejand o Ma ín Ga cía-Sancho6,
Edua do Ríos-He anz7, Josep Gumà-Pad ò8, Ma iano P o encio-Pulla9, An onio Rueda-Domínguez10,
Luis de la C uz-Me ino3,4,5* and Víc o Sánchez-Ma gale 1,2,4*
Abs ac
Backg ound Di use la ge B-cell lymphoma (DLBCL) is he mos common ype o non-Hodgkin’s lymphoma wo ld-
wide and is cha ac e ized by i s he e ogenei y. Al hough i s -line he apy imp o es su i al ou comes o DLBCL
pa ien s, app oxima ely one hi d will elapse, o en wi h a poo p ognosis. Among he ac o s in luencing p og-
nosis and esponse o ea men in cance pa ien s, including hose wi h lymphoma, o e weigh and obesi y ha e
eme ged as signi ican conside a ions. Howe e , he ole o excess weigh in DLBCL emains con o e sial, wi h s ud-
ies epo ing bo h nega i e and posi i e e ec s on cance ou comes. In his ansla ional subs udy o he R2-GDP-
GOTEL ial, we ha e e alua ed he impac o excess weigh as a p edic o o ea men esponse and su i al
in pa ien s wi h elapsed/ e ac o y (R/R) DLBCL, and examining i s ela ionship wi h immune cell dynamics.
Me hods O he 79 pa ien s who ecei ed he R2-GDP scheme in he phase II ial, weigh and heigh pa ame e s
we e ob ained in 75 pa ien s be o e s a ing ea men . Blood samples we e analyzed by low cy ome y. S a is i-
cal analyses we e pe o med o de e mine he p ognos ic alue o o e weigh and obesi y a baseline in R/R DLBCL
pa ien s.
Resul s Ou esul s indica e ha o e weigh (including obese) pa ien s exhibi longe su i al compa ed o pa ien s
o ideal weigh . This g oup also demons a ed a educ ion o egula o y T cells wi h supposedly p o umo ac i -
i y and an inc ease o Na u al Kille (NK)-like T cells wi h supposedly an i umo ac i i y. Addi ionally, we ha e
†Lou des Hon ecillas-P ie o and Daniel J. Ga cía-Domínguez au ho s
con ibu ed equally o his wo k as i s au ho s.
†Luis de la C uz-Me ino and Víc o Sánchez-Ma gale au ho s should be
conside ed as senio au ho s.
*Co espondence:
Luis de la C uz-Me ino
[email p o ec ed]
Víc o Sánchez-Ma gale
[email p o ec ed]
Full lis o au ho in o ma ion is a ailable a he end o he a icle
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Hon ecillas‑P ie oe al. Cance & Me abolism (2025) 13:12
ound ha excess weigh co ela es wi h be e ea men esponse, associa ed wi h ele a ed le els o i amin D
and CD8 + NK cells.
Conclusions Ou indings sugges ha excess weigh does no exace ba e he p og ession o DLBCL. Ins ead, i
appea s o con e a su i al ad an age and imp o e ea men esponse, wi h he immune sys em playing a possible
pi o al ole in media ing hese e ec s.
T ial egis a ion Eud aCT, ID:2014–001620-29.
Keywo ds Di use La ge B Cell Lymphoma, Response o ea men , Obesi y pa adox, CD8 + Na u al Kille cells,
Vi amin D, R2-GDP-GOTEL
Backg ound
Di use la ge B cell lymphoma (DLBCL) is he mos
common ype o non-Hodgkin lymphoma wo ldwide,
accoun ing o app oxima ely 40% [1]. This umo is
cha ac e ized by i s clinical he e ogenei y, wi h a ia-
ions in p esen a ion, esponse o he apy, and p ogno-
sis. In ecen yea s, i s -line he apies, pa icula ly hose
in ol ing i uximab combined wi h cyclophosphamide,
doxo ubicin, inc is ine, and p ednisone (R–CHOP),
ha e led o signi ican imp o emen s in su i al ou -
comes o DLBCL pa ien s. Despi e hese ad ances,
abou one- hi d o pa ien s expe ience elapse and ace
poo p ognoses, especially in cases whe e he disease
is e ac o y o ini ial o subsequen ea men s [1, 2].
Due o he he e ogenei y o di use la ge B-cell lym-
phoma (DLBCL), esea che s ace he challenge o iden-
i ying new p ognos ic ac o s ha can p edic ea men
esponse in pa ien s wi h DLBCL. Among hese ac o s,
excess weigh has eme ged as a signi ican conside a-
ion ac oss a ious umo ypes, including lymphomas.
Excess body weigh , de ined as an abno mal o excessi e
accumula ion o a , encompasses bo h o e weigh and
obesi y.
I is well-es ablished ha obesi y inc eases he isk o
de eloping mul iple malignancies. In he con ex o non-
Hodgkin lymphomas, pa icula ly DLBCL, obesi y has
adi ionally been iewed as a isk ac o [3, 4]. Mo eo-
e , excess weigh is known o wo sen p ognosis and may
in luence ea men decisions in pa ien s wi h DLBCL [5].
A me a-analysis ha pooled 203 s udies in ol ing o e 6
million cance pa ien s demons a ed ha obesi y is asso-
cia ed wi h educed o e all su i al in his popula ion
[6]. Howe e , in his and o he s udies i was obse ed
ha pa ien s wi h melanoma, lung and kidney cance [6],
b eas [7] o head and neck cance [8, 9], exhibi ed be e
su i al a es i hey we e obese. This in e se associa ion
is being called "obesi y pa adox" [10] and he unde lying
mechanisms by which obesi y migh se e as a p o ec i e
ac o o ce ain cance ypes emain unknown.
Rega ding DLBCL, he limi ed numbe o p e ious
s udies p esen mixed esul s. Some s udies ha e shown
ha DLCBL pa ien s who we e obese p io o diagnosis
had a poo e su i al ou come [11]. Con e sely, being
o e weigh o obese a he ime o DLBCL diagno-
sis has been associa ed wi h imp o ed o e all su i al
[12, 13]. While some esea ch has iden i ied a ela ion-
ship be ween excess weigh and su i al in lymphoma
pa ien s, i emains unclea whe he obesi y can in lu-
ence he ea men esponse in hese indi iduals. One
explana ion could imply ha excess weigh pa ien s p e-
sen di e ences in immune cell composi ion compa ed
o hose wi h ideal weigh , as he immune sys em plays
a c ucial ole in he p ognosis and ea men esponse o
DLBCL pa ien s [1]. Indeed, ou p e ious esul s showed
ha p omising and unde explo ed subse s o NKs,
CD8 + NKs, is associa ed wi h longe su i al and com-
ple e esponses o ea men in R/R DLBCL pa ien s [1].
In pa ien s wi h DLBCL en olled in he GOTEL clini-
cal ial, ou g oup has demons a ed ha o e weigh
indi iduals exhibi be e su i al ou comes compa ed
o hose wi h an ideal weigh . Mo eo e , a highe p o-
po ion o o e weigh pa ien s achie e a comple e
esponse o ea men . To u he in es iga e he unde -
lying easons o hese di e ences in esponse o ea -
men , we conduc ed an immunological p o iling o he
pa ien s. Ou analysis e ealed signi ican di e ences
in he CD8 + Na u al Kille (NK) cell popula ion, which
has been p e iously associa ed wi h comple e esponse
and su i al in his ea men egimen [1]. No ably, we
obse ed hese di e ences be ween pa ien s wi h ideal
weigh and hose wi h excess weigh . Addi ionally, o he
i s ime, we desc ibe a ela ionship be ween ea men
in excess weigh pa ien s, CD8 + NK cell popula ion and
i amin D le els.
Me hods
Pa ien s ande hics app o al
A o al o 79 pa ien s wi h R/R DLBCL pa icipa ed in
he R2-GDP-GOTEL phase II clinical ial (Eud aCT
Numbe : 2014–001620-29) [14]. This was a mul icen e ,
open-label, single-a m s udy. The esea ch was con-
duc ed acco ding o he In e na ional E hical Guidelines
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Hon ecillas‑P ie oe al. Cance & Me abolism (2025) 13:12
o Biomedical Resea ch In ol ing Human Subjec s, he
Decla a ion o Helsinki, good clinical p ac ice guidelines,
and local laws. The s udy p o ocol, along wi h any sub-
sequen amendmen s, ecei ed app o al om he Se ille
P o incial E hics Commi ee o Resea ch wi h D ugs.
Body mass index: pa ien s cha ac e is ics
P io o he ini ia ion o ea men , weigh and heigh
measu emen s we e collec ed om ial pa icipan s.
Body mass index (BMI) was calcula ed by di iding weigh
(kg) by heigh (m) squa ed (kg/m2) o each pa ien .
Pa ien s we e classi ied acco ding o hei BMI based on
he Wo ld Heal h O ganiza ion (WHO) as unde weigh
(BMI < 18.5 kg/m2), ideal weigh (BMI 18.5–24.9 kg/
m2), o e weigh (BMI 25–29.9 kg/m2), and obesi y
(BMI ≥ 30kg/m2) [15]. O he 79 pa ien s in he s udy,
h ee pa ien s we e disca ded because wo o hem had
no heigh o weigh da a and he o he was ule ou
because he pa ien had a BMI < 18.5kg/m2. The e o e,
he coho o cases analyzed consis ed o 75 pa ien s
whose main cha ac e is ics a e summa ized in Supple-
men a y Table1.
T ea men o pa ien s: Lenalidomide plusR‑GDP
(R2‑GDP)
Pa ien s wi h elapsed/ e ac o y (R/R) DLBCL who we e
no candida es o au ologous s em cell ansplan a ion
(ASCT) ecei ed ea men wi h a combina ion o lenalido-
mide and i uximab (R2) along wi h gemci abine, cispla in,
and dexame hasone (R2-GDP schedule). The adminis a-
ion p o ocol has been p e iously de ailed [1, 14].
Response o ea men o pa ien s
Tumo esponse was assessed using he In e na ional
Wo king G oup C i e ia [16]. Compu ed omog aphy
scan was pe o med a e he hi d induc ion cycle, and
PET scans we e conduc ed wi hin he ou weeks ollow-
ing he inal induc ion cycle. The Bes O e all Response
was used o calcula e he esponse. This e alua ion
allowed us o ca ego ize pa ien s in o comple e esponse
(CR), pa ial esponse (PR), s able disease (SD) o and
hose wi h disease p og ession (PD).
Immunopheno yping inwhole blood samples
Immune cells we e s udied in pe iphe al blood om
R/R DLBCL pa ien s du ing he R2-GDP-GOTEL s udy
a baseline ime-poin . Blood samples we e collec ed in
EDTA-K3 ubes and cell popula ions we e de e mined
by low cy ome y analysis using he BD FACSCan o
II™ low cy ome y sys em wi h he monoclonal an i-
bodies (mAbs) and p o ocols ecommended by Bec on
Dickinson Immunocy ome y Sys ems (BDIS, San Jose,
CA, USA). Lymphocy e subpopula ions we e analyzed by
BD Mu i es 6-Colo TBNK (Bec on Dickinson). mAbs
a e lis ed in Supplemen a y Table2 and he pheno ypes
o immune cell s udies a e desc ibed in Supplemen a y
Table3.
Vi amin D analysis inse um
Vi amin D le els could only be analyzed in 62 R/R
DLBCL pa ien s be o e ea men . Blood om pa ien s
was collec ed in se um sepa a o ubes and a e 30min
a es was cen i uged a 2000 pm 10min and se um
on op o he gel was collec ed in c yo ubes and s o ed
a −80°C. A he end o he R2-GDP-GOTEL s udy, all
samples we e measu ed in he same day by an au oma ed
chemiluminescence immunome ic analysis using he
Liaison® (DiaSo in, Mad id, Spain) sys em.
S a is ical analysis
Mann–Whi ney es s was used o e alua e di e ences
be ween wo g oups. Su i al cu es we e plo ed using
he Kaplan–Meie me hod and compa ed wi h he log-
ank es . The Spea man’s Rank es and p incipal com-
ponen analysis we e used o de e mine he ela ionship
be ween di e en a iables. Fishe exac es was used o
assess he associa ion be ween wo bina y a iables in a
con ingency able. All s a is ical analyses in he s udy
we e pe o med using he so wa e G aphPad P ism
(6.01) and JMP (V.10). The a e age o samples wi h SD
is p esen ed in all expe imen s. Fo all analyses,p- alues
o ≤ 0.05 we e conside ed s a is ically signi ican .
Resul s
Baseline clinical cha ac e is ics o R/R DLBCL pa ien s
acco ding oBMI
A o al o 75 pa ien s diagnosed o R/R DLBCL en olled
in he R2-GDP-GOTEL ial we e ca ego ized by BMI
in o wo g oups based on hei BMI: ideal weigh (BMI
18.5–24.9 kg/m2) and excess weigh (BMI ≥ 25 kg/m2).
The ideal weigh g oup consis ed o 25 pa ien s (median
age o 63yea s) and he excess weigh g oup included 50
pa ien s (median age o 68.6yea s). In he ideal weigh
g oup, 60% we e male and 40% we e emale and simila ly
in he excess weigh g oup, 52% we e male and 48% we e
emale. Rega ding disease s a us, 44% o he ideal weigh
g oup we e p ima y e ac o y DLBCL de ined as in
he SCHOLAR-1 s udy [17] and 52% had elapsed non-
e ac o y disease. Fo he excess weigh g oup, 38% had
e ac o y disease and 52% had elapsed non- e ac o y
disease. The cell-o -o igin subg oups (Hans algo i hm
by immunohis ochemis y) showed ha 24% o he ideal
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Hon ecillas‑P ie oe al. Cance & Me abolism (2025) 13:12
weigh g oup we e ge minal cen e B-cell (GCB), and 44%
we e non-GCB, while in he excess weigh g oup, 26%
we e GCB, and 46% we e non-GCB. In e ms o ea -
men esponse, 32% o he ideal weigh g oup achie ed
a CR and 40% had PD. In he excess weigh g oup, 42%
achie ed a CR and 26% had PD. The main baseline cha -
ac e is ics o he pa ien s a e summa ized in Supplemen-
a y Table1.
Su i al and esponse o ea men does no  a y
be weeno e weigh andobese pa ien s
We ini ially in es iga ed whe he su i al ou comes di -
e ed be ween o e weigh and obese pa ien s wi h R/R
DLBCL. Ou analysis e ealed no signi ican di e -
ences in su i al be ween hese wo g oups a 24mon hs
(p = 0,9308) o a he conclusion o he s udy (p = 0,7599)
(Fig. 1A and B). Addi ionally, no changes we e ound
be ween ali e and deceased o e weigh and obese
pa ien s wi h OS g ea e han and less han 24mon hs
(p = 0.6684), no a he end o he s udy (p = 0.8848)
(Fig.1C and D). Finally, we also examined he esponse
o ea men be ween hese wo g oups o pa ien s
wi h R/R DLBCL. The e was no di e ence in ea men
esponse be ween hese g oups o pa ien s (p = 0.1088)
(Fig.1E).
O e weigh /Obese R/R DLBCL pa ien s exhibi
longe su i al compa ed oIdeal weigh Pa ien s
Gi en ha no signi ican di e ences in su i al we e
ound be ween o e weigh and obese pa ien s, hese
wo ca ego ies we e combined in o a single g oup
e e ed o as "excess weigh pa ien s" cha ac e ized by a
BMI ≥ 25kg/m2. Fo he emainde o he s udy, compa i-
sons we e made be ween ideal weigh pa ien s and hose
wi h excess weigh .
Ou analysis e ealed ha pa ien s wi h excess weigh
demons a ed a signi ican ly highe su i al a e com-
pa ed o hose wi h ideal weigh , bo h a 24 mon hs
(p = 0.0413) and a he s udy’s conclusion (p = 0.0352)
(Fig.2A and B). Addi ionally, he p opo ion o pa ien s
wi h excess weigh who we e ali e a 24mon hs (43%) was
s a is ically g ea e han ha o pa ien s wi h ideal weigh
(28%) (p = 0.0382) (Fig.2C). A simila end was obse ed
a he end o he ea men pe iod (p = 0.0002), whe e
39% o pa ien s wi h excess weigh we e s ill ali e, com-
pa ed o jus 15% o pa ien s wi h ideal weigh (Fig.2D).
To ule ou ha he esul ob ained could be in luenced
by con ounding ac o s, we pe o med an analysis wi h
he clinical cha ac e is ics o pa ien s wi h excess weigh .
No associa ion was obse ed wi h age, sex, molecu-
la sub ypes, and e ac o y disease (Supplemen a y
Fig.1 Su i al ou come does no a y be ween o e weigh and obese pa ien s. S udy o o e all su i al be ween obese and o e weigh pa ien s
a 24 mon hs (A) and a he end o he s udy (B) using Kaplan–Meie cu es. Pe cen age o pa ien s ali e a 24 mon hs a e ea men (C) and a he
end o he s udy (D). Analysis o he pe cen age o pa ien s acco ding o ea men esponse (E)
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Hon ecillas‑P ie oe al. Cance & Me abolism (2025) 13:12
Fig.1A). These indings sugges ha excess weigh may
ac as a p edic i e ac o in R/R DLBCL pa ien s ea ed
wi h he R-GDP and lenalidomide schedule, as e idenced
by hei imp o ed su i al ou comes ela i e o hose
wi h ideal weigh .
Reduced ci cula ing egula o y T cell (T eg)
popula ion inpa ien s wi hexcess weigh
To in es iga e he unde lying easons o he imp o ed
su i al obse ed in pa ien s wi h excess weigh , we con-
duc ed an immunological p o iling analysis ocusing on
p o- umo and an i- umo immune cell popula ions in
bo h excess weigh and ideal weigh pa ien s.
Rega ding p o- umo immune cells, we ound
no signi ican di e ences be ween he wo g oups
in he subse s o myeloid-de i ed supp esso cells
(MDSCs), including monocy ic-MDSCs (M-MDSCs),
g anulocy ic-MDSCs (G-MDSCs), and o al MDSCs
(p = 0.9179 o M-MDSCs, p = 0.9069 o G-MDSCs,
and p = 0.9069 o o al MDSCs) (Fig. 3A). Howe e ,
a signi ican educ ion in he egula o y T cell (T eg)
popula ion was obse ed in pa ien s wi h excess weigh
compa ed o hose wi h ideal weigh (p = 0.0042)
(Fig. 3A). Among he an i- umo immune cells ana-
lyzed, we ound signi ican di e ences in NK-like T
cells (CD3 + CD8 + CD16 + CD56 +), a cy o oxic T cell
subse known o induce umo cell dea h. Speci ically,
NK-like T cells we e inc eased in he pe iphe al blood
o excess weigh pa ien s (p = 0.0306) (Fig.3B). No sig-
ni ican di e ences we e obse ed in he o he an i-
umo cell popula ions (Fig.3B).
Finally, we e alua ed he ela ionship o T eg and NK-
like T cells popula ions wi h su i al in obese pa ien s.
We obse ed ha o e all su i al in hese pa ien s
is posi i ely ela ed o NK-like T cells and nega i ely
ela ed o T eg cells (Supplemen a y Fig. 1B). How-
e e , his ela ionship is no signi ican (Supplemen a y
Fig.1C).
In summa y, pa ien s wi h excess weigh exhibi a
dec eased popula ion o p o- umo T eg cells and an
inc eased popula ion o an i- umo NK-like T cells,
which may con ibu e o hei imp o ed ou comes.
Fig. 2 Excess weigh pa ien s ha e longe su i al compa ed o ideal weigh pa ien s. Kaplan–Meie cu es o o e all su i al
be ween ideal-weigh and excess weigh pa ien s a 24 mon hs (A) and a he end o he s udy (B). Pe cen age o pa ien s ali e a 24 mon hs
a e ea men (C) o a he end o he s udy (D)

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Hon ecillas‑P ie oe al. Cance & Me abolism (2025) 13:12
Excess weigh inR/R DLBCL pa ien s isassocia ed
wi himp o ed ea men esponse inGOTEL ial
We nex assessed ea men esponse in he excess weigh
and ideal weigh pa ien g oups, ocusing on hose who
achie ed comple e esponse (CR) e sus hose wi h dis-
ease p og ession (PD). A signi ican ly highe pe cen age
Fig. 3 Speci ic immune cells subpopula ions be ween ideal and excess weigh pa ien s. Analysis o basal le els o p o- umo immune cells
among ideal weigh and excess weigh pa ien s (A). Analysis o basal le els o an i- umo immune cells among ideal weigh and excess weigh
pa ien s (B). Fo all he analyses, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 and ****P ≤ 0.0001. NS, no signi ican
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Hon ecillas‑P ie oe al. Cance & Me abolism (2025) 13:12
o CR was obse ed in pa ien s wi h excess weigh (60%)
compa ed o hose wi h ideal weigh (44%) (p = 0.0335)
(Fig.4A).
To explo e he immune mechanisms unde lying his
enhanced esponse o ea men , we analyzed he base-
line p o iles o p o- and an i- umo immune cell popula-
ions in bo h pa ien g oups. Rega ding p o- umo cells,
no signi ican di e ences we e iden i ied be ween CR
and PD in ei he ideal weigh o excess weigh pa ien s
(Fig. 4B). Simila ly, T lymphocy e le els did no di e
be ween hese g oups (Fig. 4B). Howe e , in he ideal
weigh g oup, an inc ease in NK-like T cells was obse ed
in pa ien s who achie ed CR compa ed o hose wi h PD
(p = 0.0151) (Fig.4B). In e es ingly, his end was no sig-
ni ican in he excess weigh g oup (Fig.4B).
Fu he analysis o an i- umo cells e ealed di e ences
only in he excess weigh g oup, whe e pa ien s who
achie ed CR had signi ican ly highe le els o o al NK
cells (p = 0.0108) (Fig.4B).
Gi en ou p e ious indings ha he CD8 + NK cell
subpopula ion is associa ed wi h CR in R/R DLBCL
pa ien s [1], we u he in es iga ed his subpopula ion in
bo h excess weigh and ideal weigh g oups. Rema kably,
he g oup o excess weigh pa ien s wi h CR had signi i-
can ly highe baseline le els o CD8 + NK cells compa ed
o hose wi h PD (p = 0.0036) (Fig.4B). No signi ican
di e ences in ea men esponse we e obse ed in he
CD8- NK subpopula ion in ei he g oup (Fig.4B).
In summa y, ou esul s sugges ha excess weigh is
associa ed wi h be e ea men esponse in R/R DLBCL
pa ien s, and ele a ed ci cula ing CD8 + NK cell le -
els a baseline a e s ongly linked o CR in his pa ien
popula ion.
High le els o  i amin D andCD8 + NK cells a e
associa ed wi hCR o ea men inexcess weigh
inR/R DLBCL pa ien s
Gi en ha i amin D may in luence ea men e icacy in
cance pa ien s [18], we i s de e mined whe he base-
line i amin D le els we e ela ed o ea men esponse.
I was obse ed ha he e is no di e ence in esponse o
ea men in ideal weigh pa ien s be ween hose who a e
i amin D de icien (< 15ng/mL) and hose who ha e su -
icien i amin D le els (> 15ng/mL) (Fig.5A). Howe e ,
he pe cen age o pa ien s wi h excess weigh and CR o
ea men p esen ed highe i amin D le els han hose
wi h PD (44% and 22% espec i ely) (Fig.5B). This ela-
ionship be ween i amin D and esponse o ea men is
no in luenced by excess weigh , since we ha e ound ha
pa ien s wi h ideal weigh ha e he same i amin D le els
as pa ien s wi h excess weigh (Supplemen a y Fig.1D).
Conside ing he obse ed ela ionship be ween i a-
min D and ea men esponse, we nex in es iga ed
he co ela ion o i amin D wi h CD8 + NK cells. Ou
analysis e ealed a posi i e co ela ion be ween i amin
D le els and CD8 + NK cells in he excess weigh g oup
(p = 0.0474) bu no in he ideal weigh g oup (p = 0.8167)
(Fig. 5C and D). Fu he mo e, pa ien s wi h su icien
i amin D le els (> 15 ng/mL) exhibi ed signi ican ly
highe NK CD8 + cell coun s han hose wi h i amin D
de iciency (< 15ng/mL) (p = 0.0316) (Fig. 5E). This ela-
ionship was no obse ed o he NK CD8- o o al NK
cell popula ions (p = 0.1873 and p = 0.5673, espec i ely)
(Fig.5E).
These indings sugges ha , in pa ien s wi h excess
weigh , baseline i amin D le els a e posi i ely co ela ed
wi h CD8 + NK cell coun s, and his ela ionship may
con ibu e o an imp o ed esponse o ea men in R/R
DLBCL pa ien s.
Discussion
Obesi y is ecognized as a isk ac o o he de elop-
men and mo ali y o nume ous diseases, including
cance . Speci ically, obesi y has been associa ed wi h an
inc eased isk o de eloping DLCBL and may also con-
ibu e o a poo e p ognosis in hese pa ien s [4, 19].
Howe e , he impac o excess weigh on su i al ou -
comes in DLBCL pa ien s emains. In ou s udy we
did no obse e any signi ican di e ences in su i al
be ween o e weigh and obese pa ien s, a inding con-
sis en wi h p e ious epo s in pa ien s wi h colon can-
ce [20] and lung cance [21].
Nume ous s udies ha e shown ha cance pa ien s
who a e obese o o e weigh o en expe ience lowe su -
i al a es, es ablishing obesi y as an ad e se p ognos-
ic ac o . Fo ins ance, Geye e al. demons a ed ha
pa ien s wi h DLBCL who we e obese p io o diagno-
sis had wo se su i al ou come [11]. Howe e , he e a e
also se e al s udies indica ing an in e se ela ionship,
whe e being o e weigh o obese a he ime o DLBCL
diagnosis is associa ed wi h imp o ed o e all su i al
[12]. These indings suppo he esul s p esen ed in
ou s udy, whe e pa ien s wi h R/R DLBCL and excess
weigh (BMI > 25kg/m2) a baseline ha e be e su i al
ou come. Fu he mo e, he pe cen age o o e weigh
pa ien s ali e a 2yea s and a he conclusion o he s udy
was highe compa ed o hose wi h an ideal weigh .
The easons why obesi y could se e as a p o ec i e ac-
o in cance pa ien s emain unclea . One possible expla-
na ion is ha excess adipose issue in cance pa ien s may
p o ide a ese e o ene gy ha helps pa ien s endu e he
disease and wi hs and he apy [22]. In con as , malnu-
i ion and unde weigh condi ions may comp omise
immune unc ion inc easing suscep ibili y o in ec-
ions, ea men - ela ed oxici y, and me as asis [8, 9].
Ano he plausible explana ion in ol es di e ences in
Page 8 o 12
Hon ecillas‑P ie oe al. Cance & Me abolism (2025) 13:12
Fig. 4 The esponse o ea men is mo e a o able in excess weigh pa ien s han in ideal weigh . Analysis o he pe cen age o ideal weigh
and excess weigh pa ien s acco ding o ea men esponse (A). S udy o basal le els o immune cells in ideal weigh (B) and o e weigh (C)
pa ien s in ela ion o esponse o he apy.Fo all he analyses, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 and ****P ≤ 0.0001. NS, no signi ican
Page 9 o 12
Hon ecillas‑P ie oe al. Cance & Me abolism (2025) 13:12
Fig. 5 High le els o i amin D is associa ed wi h CR o ea men and NK CD8 + popula ion in excess weigh pa ien s. Rela ionship o i amin
D le els o ea men esponse in ideal weigh (A) and o e weigh pa ien s (B). Co ela ion be ween basal i amin D le els and ci cula ing NK
CD8 + cells in ideal weigh (C) and o e weigh (D) pa ien s. Analysis o basal le els o o al NK cells and CD8+ and CD8− subpopula ions acco ding
o i amin D le els (< and > 15 ng/mL) (E). Fo all he analyses, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 and ****P ≤ 0.0001. NS, no signi ican