Heterogeneity and dynamics of the tumor-infiltrating lymphocyte repertoire
Isabel Poschke1, Michael Flossdorf2,Lena Appel1, Daniel Baumann1, Marta Faryna4, Jan Rieger1, Michael Volkmar1, Jessica Hassel3, Oliver Strobel3, Markus Buchler3, Ugur Sahin4, Rienk Offringa1, 3
1German Cancer Research Center, Heidelberg; 2Technical University of Munich; 3Heidelberg University Hospital; 4BioNTech Group, Mainz; Germany
The presence of tumor-infiltrating lymphocytes (TIL) is associated with prolonged survival in many cancers, and harnessing of the T-cell response through checkpoint inhibition or infusion of ex vivo expanded TILs can result in tumor regression. We characterize the TIL repertoire by T-cell receptor (TCR) deep sequencing and functional analysis in patients with melanoma, an immunogenic tumor with high mutational load, and pancreatic ductal adenocarcinoma, a tumor with intermediate numbers of mutations.
In both cancer types, the TIL TCR repertoire is dominated by highly frequent CDR3 sequences that can be up to 10.000-fold enriched in tumor as compared to peripheral blood, bearing witness to in situ clonal expansion of tumor-reactive T-cell clones. Although this pattern is consistent for each comparison between tumor biopsy and patient blood, we find significant differences between the TCR repertoires in different tumor biopsies from the same patient, and even in different biopsies from the same tumor lesion. This supports the notion that TCRs enriched within TIL represent local, non-systemic anti-tumor T-cell responses.
In vitro expansion of TILs is readily possible, also for pancreatic cancer. However, the TCR repertoire composition undergoes drastic shifts during culture, which in many cases results in loss of tumor-dominant TCRs.
Our findings call for further analysis of the heterogeneity of the TIL response in cancer patients and imply that therapeutic efficacy of TCR gene therapy using tumor-dominant TCRs would be more consistent than TIL therapy.