Monocyte-derived APCs are central to the response of PD1 checkpoint blockade and provide a therapeutic target for combination therapy

Abstract

BackgroundPD1 immune checkpoint blockade (αPD1 ICB) has shown unparalleled success in treating many types of cancer. However, response to treatment does not always lead to tumor rejection. While αPD1 ICB relies on cytotoxic CD8+ T cells, antigen-presenting cells (APCs) at the tumor site are also needed for costimulation of tumor-infiltrating lymphocytes (TILs). It is still unclear how these APCs develop and function before and during αPD1 ICB or how they are associated with tumor rejection.MethodsHere, we used B16 mouse melanoma and MC38 colorectal carcinoma tumor models, which show differential responses to αPD1 ICB. The immune composition of ICB insensitive B16 and sensitive MC38 were extensively investigated using multi-parameter flow cytometry and unsupervised clustering and trajectory analyses. We additionally analyzed existing single cell RNA sequencing data of the myeloid compartment of patients with melanoma undergoing αPD1 ICB. Lastly, we investigated the effect of CD40 agonistic antibody on the tumor-infiltrating monocyte-derived cells during αPD1 ICB.ResultsWe show that monocyte-derived dendritic cells (moDCs) express high levels of costimulatory molecules and are correlated with effector TILs in the tumor microenvironment (TME) after αPD1 ICB only in responding mouse tumor models. Tumor-resident moDCs showed distinct differentiation from monocytes in both mouse and human tumors. We further confirmed significant enrichment of tumor-resident differentiated moDCs in patients with melanoma responding to αPD1 ICB therapy compared with non-responding patients. Moreover, moDCs could be targeted by agonistic anti-CD40 antibody, supporting moDC differentiation, effector T-cell expansion and anti-tumor immunity.ConclusionThe combined analysis of myeloid and lymphoid populations in the TME during successful and non-successful PD1 ICB led to the discovery of monocyte-to-DC differentiation linked to expanding T-cell populations. This differentiation was found in patients during ICB, which was significantly higher during successful ICB. The finding of tumor-infiltrating monocytes and differentiating moDCs as druggable target for rational combination therapy opens new avenues of anti-tumor therapy design.

The role of dendritic cells in tumor microenvironments and their uses as therapeutic targets

“…Likewise, BATF3 deficiency also inactivates the responses to combined anti-PD-1 and anti-CD137 immunotherapy and the synergistic effect of poly I:C and FLT3LG ( 7 ). In addition to cDC1s, a recent study showed that moDCs, especially iNOS-producing Tip-DCs, are important in the response to PD-1 blockade ( 66 ).…”

“…Even though the presence of DCs is important for responsiveness to ICB, the functionality of DCs may improve the efficacy of this therapy. Anti-CD40 agonist antibody can promote DC differentiation and proliferation in the tumor microenvironment, resulting in systemic T-cell activation that produces a synergistic effect with ICB ( 66 - 68 ). In addition, engineered type I IFN targeting to DCs improves the functionality of DCs in antitumor immune responses and the efficacy of PD-L1 blockade ( 69 ).…”

Unraveling the Heterogeneity and Ontogeny of Dendritic Cells Using Single-Cell RNA Sequencing

“…Chow et al likewise presented that the cellular crosstalk mediated by cDC1s-derived CXCL9 and CXCR3 on T cells was pivotal for the proliferation and function of intratumoral CD8 + T cells in response to anti-PD-1 treatment. Apart from cDCs in tumor immunity, the scRNA-seq of human melanoma biopsies suggested that moDCs correlated with PD-1 responsiveness and effector T cell activity, and more importantly, targeting moDCs by anti-CD40 antibody could enhanced PD-1 ICB efficacy ( 138 ).…”

Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma

“…These increases are different from what to expect from pembrolizumab monotherapy where activated CD8 T cell counts are increased only early on, at 2 or 4 weeks after start of treatment. 15 Failed T cell priming often needs repair through APC activation 16 before successful sensitization to PD-1/PD-L1 blockade and MHC II agonism with efti plays a critical role in generating T cell immunity by activating DCs [6][7][8] As efti or any other MHC class II agonist has not been tested yet in combination with an anti-PD-1 therapy, patients started efti injections in part A of the study at cycle 5 of pembrolizumab in order not to expose the subset of patients with pembrolizumab-induced immune-related AEs in the first 3 months of exposure to a second immunostimulant. Then, as no new safety signals were seen in part A, part B patients were treated with the combination from day 1 on.…”