Stromnes et al. combined mesothelin-specific CD8+ T cell (TCRMSLN) transfer with two tumor-associated macrophage (TAM)-targeting strategies in murine pancreatic ductal adenocarcinoma (PDA). TCRMSLN cells alone increased intratumoral M1 TAMs and survival. Anti-CSF1R decreased M2 TAMs and improved intratumoral endogenous CD8+ T cell numbers but had minimal impact on TCRMSLN cells. Agonist-CD40 boosted TCRMSLN cell persistence and Ki67/GzmB levels, reduced PD-1 expression, and supported remodeling of the tumor stroma, but did not rescue IFNγ production. In human PDA, M2 TAMs correlated with CSF1/CSF1R expression.

Contributed by Alex Najibi

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to therapies, including immune checkpoint blockade. We investigated two distinct strategies to modulate tumor-associated macrophages (TAMs) to enhance cellular therapy targeting mesothelin in an autochthonous PDA mouse model. Administration of an antibody to colony-stimulating factor (anti-Csf1R) depleted Ly6Clow pro-tumorigenic TAMs and significantly enhanced endogenous T-cell intratumoral accumulation. Despite increasing the number of endogenous T cells at the tumor site, as previously reported, TAM depletion had only minimal impact on intratumoral accumulation and persistence of T cells engineered to express a murine mesothelin-specific T-cell receptor (TCR). TAM depletion interfered with the antitumor activity of the infused T cells in PDA, evidenced by reduced tumor cell apoptosis. In contrast, TAM programming with agonistic anti-CD40 increased both Ly6Chigh TAMs and the intratumoral accumulation and longevity of TCR-engineered T cells. Anti-CD40 significantly increased the frequency and number of proliferating and granzyme B+ engineered T cells, and increased tumor cell apoptosis. However, anti-CD40 failed to rescue intratumoral engineered T-cell IFNgamma production. Thus, although functional modulation, rather than TAM depletion, enhanced the longevity of engineered T cells and increased tumor cell apoptosis, ultimately, anti-CD40 modulation was insufficient to rescue key effector defects in tumor-reactive T cells. This study highlights critical distinctions between how endogenous T cells that evolve in vivo, and engineered T cells with previously acquired effector activity, respond to modifications of the tumor microenvironment.

Author Info: (1) Microbiology and Immunology, University of Minnesota Medical School ingunn@umn.edu. (2) Microbiology and Immunology, University of Minnesota Medical School. (3) University of W

Author Info: (1) Microbiology and Immunology, University of Minnesota Medical School ingunn@umn.edu. (2) Microbiology and Immunology, University of Minnesota Medical School. (3) University of Washington. (4) Fred Hutchinson Cancer Research Center. (5) Immunology, Fred Hutchinson Cancer Research Center. (6) Cancer Biology, Fred Hutchinson Cancer Research Center. (7) Microbiology and Immunology, University of Minnesota Medical School. (8) Department of Microbiology and Immunology, University of Minnesota Medical Center. (9) Experimental Pathology, Program in Immunology, Fred Hutchinson Cancer Research Center. (10) Immunology, Fred Hutchinson Cancer Research Center. (11) Fred Hutchinson Cancer Research Center.