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 (TAM) to enhance cellular therapy targeting mesothelin in an autochthonous PDA mouse model. Administration of an antibody to colonystimulating factor (anti-Csf1R) depleted Ly6Clow protumorigenic 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 IFNγ 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 howendogenous T cells that evolve in vivo, and engineered T cells with previously acquired effector activity, respond to modifications of the tumor microenvironment.
Bibliographical noteFunding Information:
I.M. Stromnes is supported by an AACR Pancreatic Cancer Action Network Career Development Award (17-20-25-STRO) and an Institutional Research Grant 124166-IRG-58-001-55-IRG65 from the American Cancer Society. Support was provided by the National Cancer Institute, CA018029 and CA033084 (P.D. Greenberg) and CA161112 (S.R. Hingorani), Giles W. and Elise G. Mead Foundation (to S.R. Hingorani), a Cancer Center Support Grant P30CA015704 Supplement (S.R. Hingorani and P.D. Greenberg) and a Pancreatic Cancer Action Network Grant 16-65-GREE (P.D. Greenberg). P.D. Greenberg receives support from Juno Therapeutics, a Celgene company
I.M. Stromnes is supported by an AACR Pancreatic Cancer Action Network Career Development Award (17-20-25-STRO) and an Institutional Research Grant 124166-IRG-58-001-55-IRG65 from the American Cancer Society. Support was provided by the National Cancer Institute, CA018029 and CA033084
R.H. Pierce reports receiving commercial research grants from Juno Therapeutics, Immunomics Therapeutics, Pulse Biosciences, and X4 Pharmaceuticals, has ownership interest (including stock, patents, etc.) in Oncosec Medical, Celgene, and Five Prime Therapeutics, and is a consultant/advisory board member for AbbVie, Calithera Biosciences, Sensei Biotherapeutics, Pulse Biosciences, and Immunomics Therapeutics. P.D. Greenberg is a consultant for Juno Therapeutics, FLX Bio, Elpiscience, and Nextech, reports receiving a commercial research grant from Juno Therapeutics, has ownership interest (including stock, patents, etc.) in FLX Bio, Elpiscience, and Nextech, is a consultant/advisory board member for Juno Therapeutics, FLX Bio, Elpiscience, and Nextech. S.R. Hingorani reports receiving a commercial research grant from Halozyme Therapeutics to Fred Hutchinson Cancer Research Center and is a consultant/ advisory board member for Halozyme Therapeutics. No potential conflicts of interest were disclosed by the other authors.
© 2019 American Association for Cancer Research.