Abstract 4424: Immunoregulatory role of club cell secretory proteins in non-small cell lung cancer
Authors: Kapoor Aakanksha Rajiv , Mittal Vivek 
Published: April 2023

Abstract
Introduction. Immune checkpoint inhibitors (ICI) particularly those targeting the PD-1/PD-L1 axis are approved for NSCLC patients. However, most patients experience little clinical benefit due to immunosuppressive barriers in the tumor microenvironment. Our goal to identify immunomodulatory agents that may overcome these barriers, led to the finding that low dose stereotactic body radiation therapy (SBRT) in combination with ICI resulted in marked tumor regression and improved survival by generating durable anti-tumor immunity (Ban et al., Nature Cancer, 2021). Unexpectedly, we uncovered that the immune-modulating functions of SBRT was acutely dependent on the secretory function of lung resident Scgb1a1+ club cells that protect the bronchioles from xenobiotic agents. Blocking club cell secretome in vivo blunted the efficacy of the combination treatment and altered myeloid cell phenotypes. These findings led to the hypothesis that radiation-induced club cell factors may synergize with ICI to attenuate immunosuppressive barriers by reducing myeloid suppressive cells.
Methods and Data. Expression of 8 highest expressed club cells secretory factors (CC10, SP-A, SP-B, SP-D, Hp, Secretoglobin 3A1, 3A 2, and 1C 1) in combination with PD-1 blockade elicited significant tumor control and improved survival of NSCLC mice. Mechanistically, the 8 club cell factors inhibit myeloid suppressor cell phenotypes as determined by reduced pSTAT3, pERK and concomitant inhibition of immunosuppressive mediators Arg1, iNOS, etc. Further screening of individual club cell factors showed that CC10 alone effectively blunted myeloid suppression activity as determined by flow cytometry for Arg1 and iNOS. Hence, CC10 can functionally alter the immunosuppressive nature of myeloid suppressor cells. The ability of CC10 in improving the efficacy of ICI in impairing tumor growth and improving survival is currently being examined.
Conclusions. Myeloid suppressor cells inhibit immune cells like T cells or NK cells leading to poor prognosis in cancer treatment. Increase in their numbers has been linked to tumor aggressiveness and low efficacy of immunotherapy. Hence, there is an unmet clinical need to specifically target these cells. Agents targeting myeloid suppressor cell accumulation and differentiation (e.g., ATRA, Vitamin D, Sunitinib, Gemcitabine, Bevacizumab, Tadalafil), are being tested in human clinical trials. However, these agents lack specificity and selectivity for myeloid suppressor cells in vivo. Therefore, our work provides the rationale for the development of CC10 as selective inhibitor of myeloid suppressor cells and has the potential for achieving a robust and durable anti-tumor immunity in NSCLC.
Citation Format: Aakanksha Rajiv Kapoor, Vivek Mittal. Immunoregulatory role of club cell secretory proteins in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4424.