TREIMM 1992 No.

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Trends in
Immunology
Spotlight
γδ T cells unveil invisible are rare. Vδ1 cells are often enriched in
solid tumors, where they retain a cytotoxic
PD1, while no other lymphocyte popula-
tions differed between 2MWT and 2MMUT
tumors phenotype and are associated with a posi- cancers (Figure 1). Focusing on MMRd
1 2, tive prognosis [3]. It is largely unknown CRC, they found that these γδ T cells were
Hui-Fern Koay and Lydia Lynch * whether well-characterized inhibitory im- also enriched in the expression of NKRs. Im-
mune checkpoint molecules, including pro- portantly, although these intratumoral Vδ1/
Tumors can evade conventional grammed cell death protein 1 (PD1) and Vδ3 T cells were PD1+, they expressed cyto-
T cell recognition by rendering the CTLA4, which are essential for restraining toxicity markers, produced IFNγ, and could
HLA class I antigen presentation antitumor CD8+ αβ T cell function, are efficiently kill 2MMUT tumors in vitro. These
system defective. In a recent study, also relevant to, and/or expressed by, findings are in line with another recent
de Vries et al. reveal γδ T cells as intratumoral γδ T cells. study by the Hayday and Swanton laborato-
key contributors to the efficacy of ries showing that responses to ICB were
Immunogenic tumors that are well infiltrated associated with enriched Vδ1 transcripts in
immune checkpoint blockade (ICB)
with lymphocytes, especially T cells, are as- nonsmall cell lung cancer [9].
against HLA-I-silenced cancers,
sociated with improved prognosis. In turn,
highlighting a novel layer of sur-
immunotherapies targeting T cells are par- The study by de Vries et al. represents a new
veillance against immune escape ticularly effective in patients with mismatch level of understanding of the full potential of
by tumors. repair-deficient (MMRd) cancers, which both ICB and γδ T cells as anticancer agents
are rich in putative neoantigens recognized [8]. It raises many fundamental questions,
γδ T cells are evolutionary conserved by CD8+ T cells via HLA-I [4]. These tumor- and perhaps the overarching one revolves
T cells that straddle innate and adaptive infiltrating CD8+ T cells are often rendered around what γδ T cells see, and react to, in
immunity and have strong antitumor po- exhausted in the harsh tumor microenvi- MMRd 2MMUT tumors. Do they need their
tential. Intratumoral γδ T cell gene signa- ronment (TME), classically characterized T cell receptor (TCR) to recognize tumors,
tures have been shown to be a favorable by high expression of inhibitory check- and are neoantigen(s) involved? What we
prognostic indicator across many inde- point molecules [5]. ICB targeting PD1/ can conclude is that Vδ1/Vδ3 T cells are
pendent studies of solid tumors, including programmed death-ligand 1 and/or CTLA4 not engaging HLA-I, or the MHC-I-like mole-
colorectal cancer (CRC) [1,2]. γδ T cells blocks these inhibitory exhaustion path- cules CD1d or MR1 on tumors, given that
exert antitumor functions through degranu- ways, unleashing tumor-specific T cell re- the expression of these antigen-presenting
lation of cytotoxic factors, secretion of proin- sponses. However, MMRd cancers often molecules requires 2M. The authors pro-
flammatory cytokines, and transactivation lose HLA-I expression due to silencing posed that PD1+ Vδ1 T cells recognize tu-
of other antitumor immune cells. Unlike or mutating 2M (2MMUT) [6]. Despite this, mors by activating NKG2D or other NKRs
αβ T cells, γδ T cells are not restricted to 2MMUT tumors retain responsiveness to and their stress ligands on tumor cells. In-
HLA–peptide antigen complexes, and they ICB therapy [7]. This suggests that CD8+ deed, PD1+ Vδ1 cells kill tumors expressing
express natural killer/cytotoxicity receptors T cells are not the sole effectors in this con- NKG2D ligands MIC-A/B most effectively
(NKRs) that recognize stress antigens text and that other immune cells are able to [8]. Blockade of NKG2D reduced their ability
upregulated by many tumor types. Thus, recognize these tumors, which are ‘invisible’ to react against most, but not all tumors and
γδ T cells are rapidly gaining attention for to CD8 T cells. did not completely prevent killing of the tu-
their potential as excellent ‘universal donors’ mors. This itself raises further questions.
for adoptive cellular therapy in cancer, be- Building upon this, de Vries et al. [8] recently First, is PD1 a marker of exhaustion on
cause they would not elicit severe graft- reported that ICB worked more effec- intratumoral γδ T cells? If so, is the recogni-
versus-host disease and could recognize tively in patients with 2MMUT compared tion of stress ligands a strong enough signal
a wide variety of different tumor types, with ‘wild-type’ (2MWT) tumors (95% ver- to cause exhaustion on Vδ1/Vδ3 T cells? Of
eliminating the need for identifying tumor- sus 62% of patients, respectively, re- note, PD1+ Vδ1 T cells were more effective
specific (neo)antigens in advance [3]. In ceived clinical benefit) [8]. This led the killers than their PD1– counterparts, sug-
humans, there are three major γδ T cell sub- authors to investigate which immune gesting that PD1 + Vδ1 cells were not
sets denoted by T cell receptor usage and cells could infiltrate 2MMUT tumors. exhausted, but were instead activated
tissue tropism. In brief, Vδ2 cells are the Leveraging the Cancer Genome Atlas, or licensed to kill. However, their activity
most abundant subset found in peripheral they showed that several MMRd was associated with clinical benefit during
blood, while Vδ1 cells are more tissue resi- tumors with 2M mutations were enriched ICB, counter-intuitively indicating that
dent, as are Vδ3 cells, although the latter for Vδ1 and Vδ3 γδ T cells that expressed blocking PD1 on γδ T cells provided

Trends in Immunology, Month 2023, Vol. xx, No. xx 1

 Trends in Immunology

B2MWT B2MMUT

?
Cancer cell
PD-1 ligands?
? Cancer
Cancer cell
Tumor PD1
cell associated VG1
neoantigens?
CD8+ αβT
TCR HLA-I
HLA-I PD1
?
? Tumor
associated NKR
neoantigens?
CD8+ αβT CD4 + ? VG1 CTLA4
αβT

VG1 γ γGG T
γGG T VG3 γ D + αβT
CD4
VG3
D + αβT
CD4

Trends in Immunology

Figure 1. Proposed scenarios incorporating new clues on T cell recognition of HLA-I-presenting versus HLA-I-silenced tumors. B2M inactivation
(B2MMUT) occurs frequently in DNA mismatch repair-deficient (MMRd) colorectal cancers (CRCs), but it is unclear how B2MMUT tumors maintain reactivity to immune
checkpoint blockade (ICB). Vδ1 and Vδ3 γδ T cells infiltrate, and are activated in, B2MMUT MMRd CRC compared with their HLA-I-sufficient (B2MWT) counterparts.
These Vδ1 and Vδ3 γδT cells are PD1+ and respond to anti (α)-PD1 and α-CTLA4 antibody treatment, contributing to the efficacy of ICB therapy in B2MMUT MMRd
CRC [8]. Abbreviation: NKR, natural killer/cytotoxicity receptor.

enhanced function. Alternatively, perhaps Furthermore, is the TME as suppressive ‘off-the-shelf’ pan-cancer adoptive cellular
only PD1+ Vδ1 T cells recognize tumors for γδ T cells as it is for αβ T cells? Given immunotherapy, while, in turn, potentially
due to the co-expression of stress ligand that CD4+ αβ T cells can modulate ICB unveiling the identity of other tumor factors
receptors only on PD1+ cells, or even efficacy in MMRd 2M MUT CRC, under- that immune cells can see.
via PD1 ligands. Thus, how PD1 block- standing the weighted contribution and/or
ade affects γδ T cells warrants further interplay of antitumor Vδ1/Vδ3 T cells Acknowledgments
investigation. relative to other immune cells within the The authors are supported by NIAID grant R01AI134861
TME is crucial because these may be col- (to L.L.) and by L’Oréal UNESCO award (to H-F.K.).
What then enables the infiltration and/or re- lectively required for optimal responses
activity of Vδ1/Vδ3 T cells toward MMRd [10] (Figure 1). Declaration of interests
2MMUT tumors, if not solely via NKG2D, or None declared by authors.

via HLA-I, CD1d, or MR1? Considering the Like many surprising and impactful studies,
1
Department of Microbiology and Immunology at the Peter
tissue tropism and observed enrichment of this one by de Vries et al. generates more Doherty Institute for Infection and Immunity, The University of
Vδ1/Vδ3 T cells within solid tumors, it is likely questions than answers, which warrants Melbourne, Melbourne, VIC, Australia
2
Department of Medicine, Brigham and Women’s Hospital,
that Vδ1/Vδ3 T cells were resident in normal follow-up because this may lead to new
Boston, Harvard Medical School, Boston, MA, USA
untransformed tissue. Many unidentified avenues for targeting γδ T cell biology
factors, from metabolites and nutrient avail- during ICB against solid tumors. It also *Correspondence:
llynch@bwh.harvard.edu (L. Lynch).
ability to tissue-associated molecules in the further spotlights a long-understudied and
https://doi.org/10.1016/j.it.2023.01.011
TME, may have then induced their infiltration perhaps underappreciated population of
and/or proliferation at the transformed site. T cells that offer striking potential as an © 2023 Elsevier Ltd. All rights reserved.

2 Trends in Immunology, Month 2023, Vol. xx, No. xx

Trends in Immunology
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