Background: Lung squamous cell carcinoma (SCC) is the second most common type of non-small cell lung cancer. Immunotherapy is a promising treatment for SCC. However, only a small proportion of unselected SCC patients are able to achieve durable clinical benefit. We leveraged the precious specimens from S1400I trial and sought to explore whether the levels and spatial distributions of tumor-associated immune cells (TAICs) in screening samples are associated with PFS, and OS.

Methods: We utilized paraffin tumor tissue provided by the SWOG bank from screening on LungMAP. 82/252 eligible SCC sample from patients treated with nivolumab plus ipilimumab (nivo+ipi; n = 35) or with nivolumab alone (nivo; n = 47) were studied. Image analysis tissue immunoprofiling was conducted using 9 markers in 2 multiplex immunofluorescence panels against cytokeratin, CD3, CD8, granzyme B, CD45RO, and FOXP3, PD1, PD-L1, and CD68. Densities of cells phenotypes (cells/mm2) were assessed and dichotomized as being high (> median) or low (≤ median) in tumor, stroma, and total compartments. Distances from malignant cells (MCs) to cell populations were measured and dichotomized as close from MCs (≤ median) and faraway from MCs (> median) and associated with clinical variables. Clinicopathologic features and data on PFS, and OS were retrieved from the CIDC portal as provided by the LungMap team. Non-parametric tests where utilized to assessment associations of cell phenotypes versus continue or categorical variables and log-rank test for survival analysis.

Results: Univariate analysis showed that higher densities of memory T cells in total compartment (HR:0.63, CI:0.40-1.00, P=0.041), antigen-experienced T cells in the stroma (HR:0.60, CI:0.37-0.96, P=0.024) and total compartment (HR:0.60, CI:0.38-0.95, P=0.023) and activated cytotoxic T cells in the tumor compartment (HR:0.55, CI:0.35-0.87, P=0.011) were associated with significative better PFS. In the nivo+ipi arm, higher ratios of cytotoxic T cells to regulatory T cells in the stroma were associated with better PFS. The spatial analysis of these TAICs showed that the presence of activated cytotoxic T cells close to the MCs (median, ≤19.27 µm) was associated with better PFS (P=0.037).

Conclusions: Our findings suggest that patients who have a detectable immunosuppressive tumor axis (PD-L1/PD1) with adequate activated cytotoxic T cells close to the tumor cells are the ideal patients for immune therapy to be targetable with these types of treatments.

Acknowledgments: Scientific and financial support for: U10CA180888, U10CA180819U24CA224285, U24CA224316, PACT, PPP and FNIH.

Citation Format: Edwin Roger Parra, Jiexin Zhang, Mary Redman, Rossana Lazcano, Piubelli Mario, Caddie Laberiano Fernandez, Renganayaki K. Krishna, Shanyu Zhang, Hong Chen, Ganiraju Manyam, Radim Moravec, Ethan Cerami, James Lindsay, Joyce Yu, Roshni Biswas, Stephen Van Nostrand, Dzifa Y. Duose, Jianjun Zhang, Roy Herbst, Gheath Al-Atrash, Kasthuri Kannan, Ignacio I. Wistuba, Scott Gettinger, Lyudmila Bazhenova, Jack Lee, Jianhua Zhang, Cara Haymaker. Infiltration and spatial distribution of immune cells are associated clinical benefit from Nivolumab and Ipilimumab for previously treated patients with stage IV squamous cell lung cancer: an immune biomarker analysis of Phase III SWOG LungMAP S1400I trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2580.