PD-1 blockade-driven anti-tumor CD8⁺T cell immunity requires XCR1⁺dendritic cells

Abstract

9CD8 + T cells are required for effective anti-PD-1 (αPD-1) cancer immunotherapy. Type 1 10 conventional dendritic cells (cDC1s) bearing XCR1 critically mediate the initiation of 11 protective anti-tumor CD8 + T cell responses in mice and humans. However, whether 12 cDC1s contribute to evoking the effector function of CD8 + T cells during αPD-1 antibody 13 therapy remains unclear. Here, by deleting cDC1s at the effector phase of αPD-1 therapy, 14we identify these cells as a crucial innate determinant for effective αPD-1 immunotherapy. 15 αPD-1 treatment unleashed cDC1s to promote anti-tumor CD8 + T cell immunity, through 16 the expansion of TCF1 + precursors and generation of TIM3 + terminally differentiated 17 effectors. Furthermore, tumor cDC1 abundance was predictive of enhanced CD8 + T cell 18 infiltration, higher survival, and improved clinical responses to αPD-1 therapy in human 19 cancer patients. Together, this study reveals the requirement for cDC1s in PD-1 blockade 20 therapy, through their ability to elicit CD8 + T cell effector responses that mediate tumor 21 control, and highlight cDC1s as an attractive cellular target to be harnessed for novel 22 immunotherapeutics. 23 3 effector axis mediates protective anti-tumor immune responses during αPD-1 46 immunotherapy. 47The initiation of anti-tumor CD8 + T cell responses requires BATF3-dependent 48 cDC1s, which are a subset of antigen presenting cells (APCs) that specializes in the 49 acquisition, processing, and presentation of tumor antigens 20 . Tumor-infiltrating cDC1s 50 traffic tumor antigens to the tumor draining lymph node (TDLN) in a CCR7-dependent 51 manner where they efficiently cross-prime tumor-specific naive CD8 + T cells 21,22,23 . In 52 addition to mediating the induction of endogenous anti-tumor immune responses, recent 53 studies have implicated an important role for cDC1s in the efficacy of checkpoint blockade 54 therapy 24,25,26,27 . In particular, it was shown that tumor-bearing mice that were 55 developmentally deficient in BATF3-dependent DCs failed to respond to αPD-1 or αPD-56 L1. The lack of an immune response to αPD-1, however, could be due to defective priming 57 of tumor-specific T cells by DCs during early stages of tumor development, and does not 58 reflect the requirement of cDC1s during immunotherapy. Therefore, the role of cDC1s 59 independent of early TDLN priming and their impact on activated, antigen-experienced 60 CD8 + T cells during αPD-1 therapy remain unclear. Here we probe the role of cDC1s 61 during the effector stage of αPD-1 cancer immunotherapy. 62 63Results 64 XCR1 + cDC1s are required for effective anti-PD-1 immunotherapy against 65 established murine melanoma 66We first examined the presence of tumor-infiltrating cDC1s using a melanoma 67 model B16.F10 expressing the lymphocytic choriomeningitis virus glycoprotein epitope 68 4 GP33-41 (B16.GP33). cDC1s were identified by their surface expression of I-A/I-E, 69CD11c, XCR1, and CD24, representing a distinct APC compartment in the tumor 70 ( Supplementary F...

A unified atlas of CD8 T cell dysfunctional states in cancer and infection

“…Interestingly, cells in cluster 9 preferentially expressed genes induced during the early hours of T cell activation ("early response genes"), such as Xcl1, Cd200, Cxcl10, Cd69, Tnfsf8 ( Figure 4E,G, Supplementary Figure 13A) (46)(47)(48)(49)(50)(51). Xcl1 was the most strongly enriched gene in cluster 9; this gene was previously shown to be activated very early after antigen encounter and to be critical for engagement with antigen-presenting dendritic cells via Xcr1 (48,49,52); consistently, Xcr1+ dendritic cells were shown critical for promoting anti-tumor CD8 T cell immunity by anti-PD1 therapy via expansion of progenitor dysfunctional cells (53). On the other hand, many genes overexpressed in cluster 9 were also enriched in naïve cells, including Tcf7, Id3, Slamf6, Dapl1, Ccr7, Nsg2 ( Figure 4E,G, Supplementary Figure 13A).…”

Vectorized Treg-depleting αCTLA-4 elicits antigen cross-presentation and CD8+ T cell immunity to reject ‘cold’ tumors

“…Besides mediating induction of endogenous antitumor immune responses 16 and efficacy of systemic checkpoint blockade therapy, 35 44 45 cDC1s promote the proliferative response of intratumoral CD8 + TILs, expand the pool of TCF1 + stem-like precursors, and induce generation of TIM-3 + terminal effectors during αPD-1 therapy. 46 Similarly, Treg depletion achieved with mAb to costimulatory or coinhibitory receptors, for example, IL-2R and CTLA-4, may promote CD8 + effector function and synergize with αPD-1. 47 48 With regard to development of 'dual activity' immune modulatory antibodies that reduce Treg and expand antitumor CD8 + T cells, accumulating data demonstrate the importance of both target biology, fine-tuning of effector CD8 + T cellenhancing and Treg-depleting properties, as well as delivery regimen.…”

Tumor-infiltrating dendritic cell states are conserved across solid human cancers

“…Experimental evidence suggests that tumor-infiltrating cDC1s can foster tumor control in different ways, including production of the chemokines CXCL9 ( Chow et al, 2019 ) and CXCL10 ( Spranger et al, 2017 ) that recruit CD8 + T cells to tumors and enable local (re)activation of these cells through antigen cross-presentation ( Spranger et al, 2017 ; Chow et al, 2019 ), and through production of various factors such as IFN-λ ( Hubert et al, 2020 ). cDC1s are also required for successful immunotherapy in various murine tumor models ( Moynihan et al, 2016 ; Salmon et al, 2016 ; Sánchez-Paulete et al, 2016 ; Mao et al, 2020 ; Morrison et al, 2020 ). Accordingly, cDC1 gene expression signatures in human tumors often correlate with improved patient survival and clinical response to immunotherapy ( Böttcher et al, 2018 ; Barry et al, 2018 ).…”