Quantitative tissue analysis and role of myeloid cells in non-small cell lung cancer.

Background: Despite the prominent role of innate immunity in the antitumor response, little is known about the myeloid composition of human non-small cell lung cancer (NSCLC) with respect to histology and molecular subtype. We used multiplexed quantitative immunofluorescence (QIF) to measure the distribution and clinical significance of major myeloid cell subsets in large retrospective NSCLC collections.
Methods: We established a QIF panel to map major myeloid cell subsets in fixed human NSCLC including 4',6-Diamidino-2-Phenylindole for all cells, pancytokeratin for tumor-epithelial cells, CD68 for M1-like macrophages; and CD11b plus HLA-DR to interrogate mature and immature myeloid cell populations such as myeloid derived suppressor cells (MDSCs). We interrogated 793 NSCLCs represented in four tissue microarray-based cohorts: #1 (Yale, n=379) and #2 (Greece, n=230) with diverse NSCLC subtypes; #3 (Yale, n=138) with molecularly annotated lung adenocarcinomas (ADC); and #4 (Yale, n=46) with patient-matched NSCLC and morphologically-normal lung tissue. We examined associations between marker levels, myeloid cell profiles, clinicopathologic/molecular variables and survival.
Results: The levels of CD68+ M1 like macrophages were significantly lower and the fraction of CD11b+/HLA-DR- MDSC-like cells was prominently higher in tumor than in matched non-tumor lung tissues. HLA-DR was consistently higher in myeloid cells from tumors with elevated CD68 expression. Stromal CD11b was significantly higher in squamous cell carcinomas (SCC) than in ADC across the cohorts and EGFR-mutated lung ADCs displayed lower CD11b levels than KRAS-mutant tumors. Increased stromal CD68- and HLA-DR-expressing cells was associated with better survival in ADCs from two independent NSCLC cohorts. In SCC, increased stromal CD11b or HLA-DR expression was associated with a trend towards shorter 5-year survival.
Conclusions: NSCLCs display an unfavorable myeloid immune contexture relative to non-tumor lung and exhibit distinct myeloid-cell profiles across histologies and presence of major oncogenic driver-mutations. Elevated M1-like stromal proinflammatory myeloid cells are prognostic in lung ADC, but not in SCC.
Competing Interests: Competing interests: BSH reports research funding from Neximmune and has served as a consultant for AstraZeneca and Ideaya. FVE has received a research grant from Chilean National Fund for Scientific and Technological Development (FONDECYT grant nº 1221415). MFS took part in an advisory board for Numab and BMS; reports speaker honorarium from MSD and Replimune; reports a research grant from Roche. JY is employed by Abbvie. DLR reports research support from Amgen, Cepheid, Navigate BioPharma, NextCure, Konica/Minota, instrument support from Akoya, royalty from Rarecyte, major honoraria from consultative activities with Cell Signaling Technology, Cepheid, Danaher, and Konica/Minolta, and minor honororia from consultative activities with Amgen, AstraZeneca, Fluidigm, GSK, Immunogen, Lilly, Merck, Monopteros, Nanostring, NextCure, Odonate, PAIGE.AI, Regeneron, Roche, Sanofi, Ventana, and Verily. In the past year, L.C. has been a scientific founder, consultant, and board member for NextCure, Junshi, Normunity, Tayu, Zai Lab, Tpioneer, Vcanbio, and GenomiCare and has sponsored research funds from NextCure, Normunity, and DynamiCure. RSH is on the Board of Directors of Immunocore and Junshi Pharmaceuticals and reports consultative activities with AstraZeneca, Bolt Biotherapeutics, Bristol-Myers Squibb, Candel Therapeutics, Inc., Checkpoint Therapeutics, Cybrexa Therapeutics, DynamiCure Biotechnology, LLC, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Genentech, Gilead, HiberCell, Inc, I-Mab Biopharma, Immune-Onc Therapeutics, Inc., Immunocore, Janssen, Johnson and Johnson, Loxo Oncology, Merck and Company, Mirati, NextCure, Novartis, Ocean, Biomedical, Inc, Oncocyte Corp, Oncternal Therapeutics, Pfizer, Regeneron Pharmaceuticals, Revelar Biotherapeuitcs, Inc, Ribbon Therapeutics, Roche, Sanofi, Xencor, Inc. RSH reports research support from AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck and Company. RSH serves a leadership role for the American Association for Cancer Research, International Association for the Study of Lung Cancer, Society for Immunotherapy of Cancer, and Southwest Oncology Group. KAS reports research funding from Navigate Biopharma, Tesaro/GlaxoSmithKline, Moderna, Takeda, Surface Oncology, Pierre-Fabre Research Institute, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Ribon Therapeutics, Boehringer-Ingelheimer, Akoya Biosciences and Eli Lilly. KAS has received honoraria for consultant/advisory/speaker roles from Moderna, Shattuck Labs, Pierre-Fabre, AstraZeneca, EMD Serono, Ono Pharmaceuticals, Clinica Alemana de Santiago, Dynamo Therapeutics, PeerView, AbbVie, Fluidigm, Takeda Pharmaceuticals, Merck Sharp & Dohme, Bristol Myers Squibb, Agenus, Parthenon Therapeutics, OnCusp and Torque Therapeutics.
(© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)