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2538 PD-1 Expression By Dendritic Cells Is a Key Regulator of T-Cell Immunity in Cancer

Program: Oral and Poster Abstracts
Session: 201. Granulocytes, Monocytes, and Macrophages: Poster II
Hematology Disease Topics & Pathways:
Fundamental Science, Research, immune mechanism, immunology, Biological Processes
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Rushil Shah1*, Konstantinos Aliazis, PhD1*, Anthos Christofides, MD1,2*, Angelique A Pham1*, Rinku Pal, BS1* and Vassiliki A Boussiotis, MD, PhD1

1Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
2Medicine, Yale University, New Heaven, CT

Programmed cell death 1 (PD-1) is an inhibitory receptor expressed on a variety of immune cells and a therapeutic target of checkpoint immunotherapy for cancer patients. PD-1 engagement by PD-L1 or PD-L2 can inhibit activation and expansion of tumor antigen-specific T cells. PD-1 expression in tumor-associated macrophages (TAM) correlates with impaired phagocytosis and antigen presenting function and enhanced immunosuppression. PD-1 is also expressed in dendritic cells (DC) and has been shown to correlate negatively with the outcome of DC-based cancer vaccines. On DC, PD-1 can interact with PD-L1 in cis when both of these receptors are expressed on the same cell surface. DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, and PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Very little is known about the specific role of PD-1 on DCs function. In the present study, we sought to understand the role of PD-1 on DCs in the context of cancer. We generated mice with conditional targeting of the Pdcd1 gene (encoding for PD-1) and crossed them with CD11cCre (Pdcd1f/fCD11cCre) or Clec9Cre (Pdcd1f/fClec9Cre) resulting in specific deletion of PD-1 in DC cells. We used the MC17 fibrosarcoma syngeneic mouse model to investigate the tentative implications of DC-specific PD-1 ablation on anti-tumor responses. We found larger tumor sizes and weights in tumor-bearing Pdcd1f/fCD11cCre mice compared to their Pdcd1wt/wtCD11cCre control counterparts. Pdcd1f/fCD11cCre tumor-bearing mice had significantly higher fractions of DCs in spleens and tumor-draining lymph nodes (tdLNs) but only minimal differences in their activation state and checkpoint marker expression. Similarly, CD4+ and CD8+ T cells from spleens and tdLNs were comparable in percentages and activation states. However, characterization of the immune cells at the tumor site, indicated that Pdcd1f/fCD11cCre tumor-bearing mice had a more immunosuppressive tumor microenvironment with increased fractions of CD11b+Ly6ChiLy6G-monocytic myeloid derived suppressor cells (M-MDSCs) compared to control tumor-bearing mice. Moreover, flow cytometric analysis revealed that intratumoral M-MDSC in Pdcd1f/fCD11cCre mice displayed enhanced expression of PD-L1 and CD38, consistent with a more activated and more immunosuppressive phenotype. Characterization of tumor infiltrating CD4+ and CD8+ T cells also revealed vast differences in composition and activation states. Specifically, Pdcd1f/fCD11cCre mice had larger populations of intratumoral CD3+ T cells, with a greater CD4/CD8 T cell ratio, and higher percentages of CD4+ T regulatory cells. Conversely, intratumoral CD8+ T cells were reduced, and were characterized by diminished expansion of CD8+ T effector cells, and a less activated phenotype as determined by lower expression of CD25, CD69, and GITR. In syngeneic tumor experiments with B16 melanoma expressing ovalbumin (B16-Ova), Pdcd1f/fCD11cCre mice and Pdcd1f/fClec9Cre mice similarly had greater tumor sizes and weights compared to their control counterparts. These results indicate that selective ablation of PD-1 in DCs cells confers a more immunosuppressive tumor microenvironment by promoting T regulatory cell expansion and diminishing CD8+ T effector cell activation compromising anti-tumor responses.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH