Project Abstract Despite the incredible diversity of potential T cell receptor (TCR) sequences, some are found widely in the population; these are called "public TCRs" (pTCRs). There is a growing awareness that pTCRs may sometimes play important functions; for example, they have been linked to long term control of HIV. We have found 3 "special-pTCRs" (spTCRs) that are the subject of this proposal. As we show, the presence of these spTCRs in the peripheral blood of cancer patients is highly associated with improved progression free survival and overall survival in certain groups of patients. In this R21 proposal, we will thoroughly interrogate the predictive power of spTCRs and characterize the cells that express them. Specific Aim 1: To evaluate the prognostic value of spTCRs in diverse cohorts of cancer patients receiving immunotherapy. We hypothesize the presence of spTCRs will be associated with improved clinical outcomes in lung cancer, renal cell carcinoma and melanoma patients treated at our institution, as well as patients treated on Cancer Immunotherapy Trials Network trials. We hypothesize that the predictive value of these spTCRs will be highest in patients treated with checkpoint inhibitors. Specific Aim 2: To identify the specificity and immunophenotypic features of spTCRs. Using a combination of bead and flow-based cell sorting we will enrich spTCRs from PBMC for paired single- cell TCR and RNA sequencing analysis to determine their phenotype and paired αβ sequence. Using the αβ paired sequence, we will determine their specificities. By identifying the correct phenotype, other cancer specific pTCRs may be identified for use as biomarkers or therapeutics.