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.