431 The role of Ly6cHigh macrophages in mediating anti-CTLA4 response in immune-hot DNA mismatch repair-deficient tumors
Year: 2026
Type: conference-abstract
Abstract: Background Immune checkpoint inhibitors (ICIs), including anti-PD1 and anti-CTLA4 therapies, have revolutionized cancer treatment by potentiating patients’ anti-tumor immune responses. The DNA mismatch repair (MMR) pathway corrects mismatched base pairs arising during DNA replication. Notably, patients with MMR-deficient (dMMR) tumors exhibit improved response to anti-PD1 therapy compared to patients with MMR-proficient (pMMR) tumors, regardless of cancer type. Furthermore, anti-PD1/CTLA4 combination therapy has demonstrated durable clinical benefit compared to anti-PD1 monotherapy in CheckMate-8HW, leading to its approval in metastatic dMMR colorectal cancer. However, the mechanism underlying the enhanced efficacy of anti-CTLA4 therapy in the context of dMMR tumors has not been defined. Previously, we demonstrated that inducing MMR deficiency in an ICI-refractory, pMMR murine neuroblastoma model sensitizes tumors to anti-CTLA4 therapy while maintaining resistance to anti-PD1 therapy. Here, we investigate how MMR deficiency reshapes the tumor immune microenvironment to promote anti-CTLA4 responsiveness.Methods MMR repair deficiency was induced in the murine neuro-2a cell line by knocking out MLH1 expression using CRISPR/Cas9. pMMR or dMMR tumors were grown subcutaneously in syngeneic immunocompetent A/J mice. The tumor immune microenvironment was characterized by flow cytometry, focusing on T-cells and myeloid cells. The contribution of Fc-dependent mechanisms to anti-CTLA4 efficacy was evaluated by comparing the efficacy of anti-CTLA-4 clones (9H10 and 4F10) against dMMR tumors (n = 12-15) and by depleting macrophages with clodronate liposomes before treatment (n = 9-13).Results dMMR tumors exhibited increased T-cell infiltration compared to pMMR tumors; however, T-cell activation states were comparable, suggesting that enhanced anti-CTLA4 responsiveness was not solely driven by increased T-cell priming. Instead, anti-CTLA4 efficacy in dMMR tumors was dependent on Ly6c High macrophages, as their depletion abrogated therapeutic responses. Ly6cHigh macrophages promoted Fc-dependent effector functions, resulting in regulatory T-cell depletion and increased ICOS+ T-cells following anti-CTLA4 treatment. Mechanistically, dMMR neuro-2a cells induced greater FcγRIV expression on macrophages compared to pMMR cells in vitro, consistent with elevated FcγRIV expression on Ly6cHigh macrophages within dMMR tumors.Conclusions Our findings reveal that MMR deficiency sensitizes tumors to anti-CTLA4 therapy through a macrophage-dependent mechanism. dMMR tumors promote FcγRIV expression on Ly6c High macrophages, enabling Fc-dependent depletion of regulatory T-cells and enhanced anti-tumor immune responses following CTLA4 blockade. These findings provide new insight into the immune mechanisms underlying anti-CTLA4 responsiveness in dMMR tumors.
Authors: Megan M Y Hong, Rene Figueredo, Saman Maleki
Institutions: Western University, Ontario Institute for Cancer Research
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225321628