Intratumor heterogeneity and clonal distribution of tumor-infiltrating lymphocytes revealed by multiregional T and B cell receptor repertoires in gastric cancer

Tumor-infiltrating lymphocytes (TILs) recognizing tumor neoantigens can be harnessed as a better prognosis for several human tumors. T and B cell receptor (TCR and BCR) repertoires are the key elements served as tags to track TILs in tumor immune microenvironment. This study intended to simultaneously profile TCR and BCR repertoires via ultra-deep sequencing of multiple tumor regions, adjacent normal mucosa tissues and peripheral blood from five gastric cancer (GC) patients. In parallel, immune-related molecule expression was evaluated for the immunological condition in multiregional tumors by real time-polymerase chain reaction (RT-PCR) and immunohistochemistry. We found that TILs and clonality with majority of T and B cell clones were restricted to each GC regions, obviously different with those of adjacent normal mucosa tissues and peripheral blood, representing T and B cells could react to tumor antigens and delineate the heterogeneity of tumor microenvironment. Especially for BCR repertoires, clonal amplification of B cells dispersedly congested in intratumor regions. There is no correlation between TCR and BCR repertoires in the same GC patient, suggesting that there was a spatio-temporal heterogeneity in GC immune microenvironment. These results suggested that spatially dependent and functionally diverse lymphocyte clones existed in individual GC, expanding our understanding of the adaptive immune response in GC patients.