In recent years, it has been demonstrated that immunotherapy is an effective strategy for the management of solid tumors. The origins of immunotherapy can be traced back to the work of William Coley, who elicited an immune response against sarcoma by injecting patients with a mixture of dead bacteria. Significant progress has been made since, with immune markers within the tumor now being used as predictors of cancer prognosis and manipulated to improve patient survival. While surgery remains central to the management of most patients with solid malignancies, it is important that surgeons consider the different immunotherapy strategies that can be employed to manage disease. Here, we highlight how the immune system influences tumorigenesis and bring attention to how current and future immunotherapies can serve as an adjunct to surgery.

BACKGROUND: There is increasing literature emerging on the significance of tumor-infiltrating lymphocytes in colorectal cancer. However, there have been inconsistent findings, secondary to small patient numbers and varied methods for identifying these lymphocytes. OBJECTIVE: The aim of this study was to determine the prognostic and predictive power of tumor-infiltrating lymphocytes in colon, rectal (in neoadjuvant setting), and metastatic colorectal cancer. DATA SOURCES: A comprehensive search of PubMed and Embase was undertaken from January 2006 to December 2016. STUDY SELECTION: The inclusion criteria included a description of the tumor-infiltrating lymphocyte subset(s) assessed with reporting of associated short- and long-term outcomes. MAIN OUTCOME MEASURES: The main outcome measures, were disease-free and overall survival. RESULTS: A total of 25 studies were included, 15 for primary colorectal cancer (4719 patients), 7 for locally advanced rectal cancer (727 patients), and 3 studies for metastatic colorectal cancer (418 patients). High CD3+, CD8+, FoxP3+, and CD45RO+ densities were associated with improved overall survival for primary colorectal cancer, with pooled estimated HRs of 0.88, 0.81, 0.70, and 0.63 (all p < 0.001) respectively. Furthermore, in locally advanced rectal cancer, the levels of CD8+ cells were a significant predictor of good tumor regression grade after chemoradiotherapy. LIMITATIONS: The retrospective nature of included studies and the significant interstudy heterogeneity were limitations. CONCLUSIONS: There is increasing evidence that tumor-infiltrating lymphocytes play an important role in predicting prognosis in colorectal cancer and tumor regression after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Clinical researchers are now in a unique position to build on this work to identify robust predictive markers to stratify patients not only to currently available therapies but also to immunotherapy, which has demonstrated success in improving patient outcomes.

Purpose The presence of tumor-infiltrating lymphocytes (TILs) in tumors is superior to conventional pathologic staging in predicting patient outcome. However, their presence does not define TIL functionality. Here we developed an assay that tests TIL cytotoxicity in patients with locally advanced rectal cancer before definitive treatment, identifying those who will obtain a pathologic complete response (pCR). We also used the assay to demonstrate the rescue of TIL function after checkpoint inhibition blockade (CIB). Patients and Methods Thirty-four consecutive patients were identified initially, with successful completion of the assay before surgery in those 17 patients who underwent full treatment. An in vitro cytotoxic assay of rectal cancer tumoroids cocultured with patient-matched TILs was established and validated. Newly diagnosed patients were recruited with pretreatment biopsy specimens processed within 1 month. Evaluation of TIL-mediated tumoroid lysis was performed by measuring the mean fluorescence intensity of cell death marker, propidium iodide. CIB (anti–programmed cell death protein 1 [anti–PD-1] antibody) response was also assessed in a subset of patient specimens. Results Six of the 17 patients achieved an objective pCR on final evaluation of the resected specimen after neoadjuvant chemoradiotherapy. Cytotoxic killing identified the pCR group with a higher mean fluorescence intensity (27,982 [95% CI, 25,340 to 30,625]) compared with the non-pCR cohort (12,428 [95% CI, 9,434 to 15,423]; p < .001). Assessment of the effectiveness of CIB revealed partial restoration of cytotoxicity in TILs with increased PD-1 expression with anti–PD-1 antibody exposure. Conclusion Evaluating TIL function can be undertaken within weeks of the diagnostic biopsy, affording the potential to alter patient management decisions and refine selection for a watch-and-wait protocol. This cytotoxic assay also has the potential to serve as a platform to assist in the additional development of CIB.