Immune analysis of lymph nodes in relation to the presence or absence of tumor infiltrating lymphocytes in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with unmet medical needs. Several studies have proved that high levels of tumor infiltrating lymphocytes (TILs) at diagnosis of TNBC confer better prognosis and patients respond better to specific chemotherapies. Nonetheless, current evidence suggests that only 15% of TNBC patients have very high levels of TILs, and another 15% lacks TILs. One possible reason to explain why patients have low TILs at diagnosis is that lymphocytes might be deactivated by an immune checkpoint in local lymph nodes, provoking their retention in there as they are unresponsive to other immune stimuli. We have identified 15 high TILs (≥50%) and 20 low TILs (≤5%) TNBC patients with localised tumour (T1c-T2N0M0) and compared the protein expression of five immune checkpoints in lymph nodes. We have also performed a customised 50-immune gene NanoString expression panel, the NanoString 360 Breast Cancer panel, and whole exome sequencing for mutation and neoantigen load analyses. In low TILs, we observed higher expression of CTLA-4 in local lymph nodes, which could explain why lymphocytes get retained in there and do not migrate to tumour. These patients have also higher neoantigen load and higher expression of B7.H3 and B7.H4 in the tumour. In high TILs, we observed more PD-L1+ tumour cells and more expanded humoral response. These results could provide a strategy to revert low tumour immune infiltration at diagnosis of TNBC, improving their prognosis.

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Déclaration de conflit d'intérêts

Conflict of interest statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: A.Q. received transportation and accommodation fees from MSD outside the submitted work. V.P. has received fees as consultant, participated in advisory boards or received travel grants from Sysmex, Roche, MSD, AstraZeneca and Genomic Health. A.P. has received personal fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo; fees as a consultant from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD and Lilly; grants from Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, MedSIR, Celgene, Astellas and Pzifer; is a member of the executive board of Reveal Genomics, SL, Beast International Group (BIG) and SOLTI cooperative group; and in the patronage committee of SOLTI Foundation and Actitud Frente al Cáncer Foundation. R.D. has declared advisory role for Roche, Boehringer Ingelheim, has received a speaker's fee from Roche, Ipsen, Amgen, Servier, Sanofi, Merck Sharp & Dohme, and research grants from Merck and Pierre Fabre. P.S. has received personal fees and fees as a consultant from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma and Roche; grants from Astellas, AstraZeneca, Genentech, Novartis, Oncogenex and Roche. C.G. reports grants from Roche and Pfizer; and received personal fees from Daichii Sankyo, MSD, Astra Zeneca, outside the submitted work. J.P-G. has received fees as a consultant from Roche and Eli Lilly; and travel and accommodation expenses from Roche. E.M-C. has received travel and accommodation fees from BMS and MSD; personal fees and fees as a consultant from Novartis, Roche, BMS, MSD, Pier Fabre and Sanofi. L.M-A. has received consultancy from Roche; received an educational grant and travel from BMS; holds a research collaboration with NanoString Technologies; and received grants to the Institution from Grifols, Gilead, MSD, Jansen and AbbVie. J.C. has received fees as a consultant from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, MSD, GSK, Leuko; personal fees from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MSD, Daiichi Sankyo; research funding from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardanth health, MSD, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London, Seagen; and owns stock, patents and intellectual property from MedSIR. T.M., G.V., L.P., P.G., M.M., J.B.-H., C.A. and M.V. declare no competing interests.