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New Strategy Boosts Microenvironment to Promote Antitumor Immunity in GI Metastases

Ajay V. Maker, MD, FACS
Published: Monday, Jul 31, 2017
UI HealthAjay V. Maker, MD, FACS
 
Associate Professor, Surgery
The University of Illinois at Chicago
Chicago, IL
Strategic Partnership
Despite the promise of immunotherapy for treating patients with advanced cancers, the success of using such therapies for progressive gastrointestinal (GI) malignancies such as colorectal liver metastases (CRLM) has been limited so far. Previous research suggests that success has been restricted, in part, by a lack of known colon cancer-specific tumor antigens, dose-limiting toxicity, and immunoediting. Our team at the University of Illinois at Chicago (UIC) is approaching this problem by addressing the tumor microenvironment rather than identifying specific tumor antigens. We are looking to support immunostimulation of naturally occurring tumor-infiltrating lymphocytes (TILs) in the tumor environment.

In findings published in Cancer Research,1 we reported on preclinical study results that demonstrate a novel ability to decrease the growth of liver metastases from colon cancer using immunotherapy. Specifically, the results confirm that delivery of a therapeutic immune-stimulating cytokine called LIGHT caused T cells to traffic to tumors, resulting in tumor-specific immunity.

It was particularly exciting to observe a profound antitumor immune response without the addition of any other chemotherapy or intervention. To our knowledge, this is the first study to evaluate the effect of LIGHT expression in the tumor microenvironment on the growth of metastatic liver tumors from a primary colon cancer.

Focusing on Immune Genes

In our lab, we focused on LIGHT after evaluating specific immune-related genes overexpressed in resected CRLM and determining that increased LIGHT expression was associated with improved patient outcomes.

LIGHT is an acronym for a cytokine homologous to lymphotoxins (“L”) that shows inducible expression (“I”) and competes with herpes simplex glycoprotein D (“G”) for HVEM (“H”), a receptor expressed by T lymphocytes (“T”). HVEM, or herpesvirus entry mediator, is a member of the tumor necrosis factor superfamily encoded by the TNFRS14 gene.2,3

The rationale for the LIGHT study was built on the premise that immunotherapy may play a viable role in treating patients with advanced GI malignancies and on 2 principles substantiated in prior studies: first, that the presence of activated and proliferating T cells within primary colon tumors is associated with improved survival, and second, that CRLM at baseline have low levels of both TILs and LIGHT expression.

In a prior study, we conducted microarray gene analysis on liver tumor specimens from 96 patients who had undergone resection for CRLM. It was discovered that increased LIGHT expression was highly associated with improved overall survival (OS) and recurrence-free survival (RFS; P ≤.01).4 Additionally, we determined that increased expression of TILs and higher levels of LIGHT expression on TILs were associated with improved OS and RFS.

Thus, we hypothesized that increasing LIGHT expression in the tumor microenvironment could enhance T-cell infiltration of colorectal tumors and liver metastases.

To test this theory, we established syngeneic colon cancer cell tumors in a mouse model in which the animals had an intact and unedited immune system.

Tumors in which LIGHT was overexpressed demonstrated an influx of T cells that resulted in rapid and durable tumor regressions, even after LIGHT was removed. In animals with colorectal liver metastases, expression of LIGHT similarly provoked a potent immune response that caused a significant decrease in tumor burden.

These findings potentially address the factors mentioned previously that have limited the successful use of immunotherapy to treat CRLM— lack of specific antigens and toxicity—because the intervention manipulates the body’s natural defenses to fight the tumor in the same way it has been trained to attack other foreign invaders.


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