Localization and Density of Immune Cells in the Invasive Margin of Human Colorectal Cancer Liver Metastases Are Prognostic for Response to Chemotherapy

Abstract

Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC. Cancer Res; 71(17); 5670-7. Ó2011 AACR.

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

“…Nevertheless, these tumors contain immune infiltrates, and increased numbers of tumor-infiltrating CD8 + T cells are positively associated with overall survival and response to chemotherapy, 33 , 34 indicating that intra-tumoral T cell immunity is an important determinant of LM-CRC progression. In addition, MMR-proficient LM-CRC are immunologically distinct from primary CRC in terms of immune infiltration.…”

The Immune Microenvironment of Human Tumors: General Significance and Clinical Impact

“…It is striking that the immune score is the strongest prognostic factor for survival in patients with colorectal cancer [15][16][17][18]. Whether at a metastatic stage tumors have escaped immunity is still an open question although emerging observations indicate that the metastatic immune microenvironment may still impact cancer evolution [19][20][21]. Finally, accumulation of therapeutic successes, even at advanced cancer stages, of immunomodulatory drugs such as anti-CTLA-4 [22], PD-1 [23] or PDL-1 [24] antibodies which unlock natural immune reactions support the concept that immunity is involved all along the disease [25].…”

CXCR4–CXCL12–CXCR7, TLR2–TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients

“…TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. 48 Albeit limited by the sample size, the present study demonstrated that high CXCR4 and Mut-KRAS identifies the worst prognostic group within a homogeneous cohort of mCRC with resectable liver metastases undergone to common neoadjuvant therapy. We speculate that the new class of CXCR4 antagonists recently developed 49 may be highly effective in Mut-KRAS CRLMs targeting CXCR4-positive cancer cells and improving T cell access by reducing tolerogenic effect and improving immune response in CRLM patients. )…”