Immunoscore Predicts Metastasis, Survival

Alexander M. Castellino, PhD

March 07, 2016

Immunoscore — a scoring system to determine specific lymphocyte populations in the core of the tumor and at its invasive margins — is emerging as a prognostic marker in colorectal cancer (CRC), according to researchers.

A new study shows that the test can predict survival in cancer patients with brain metastasis.

"Immunoscore is a standardized assay to quantify the density of T cells and cytotoxic T cells within the tumor microenvironment and is of powerful prognostic and predictive value," corresponding author Jérôme Galon, MD, of INSERM and the Laboratory of Integrative Cancer Immunology, Paris, France, told Medscape Medical News.

Although the concept of Immunoscore has been around for a few years, it has been known mainly within research circles. Now a company is working to commercialize the concept, which may increase its usefulness to clinicians.

Two new studies in CRC and brain metastasis have provided additional information from the analyses of patient tissue samples that validate Immunoscore's significance as a prognostic and predictive marker.

One expert likes the concept. "The uptake of this technology will be powerful to identify patients at an early stage of the disease who are likely to experience metastases and treat them more aggressively early," Bernard A. Fox, PhD, of the Providence Cancer Center, Portland, Oregon, told Medscape Medical News. Dr Fox is past president of Society of Immunotherapy of Cancer, which has sponsored a trial to validate Immunoscore.

The Colorectal Cancer Study

In the first study, published online in Science Translational Medicine, researchers showed that Immunoscore significantly predicted metastasis and even survival in patients with CRC. In contrast, data on tumor driver mutations and on cancer pathway–related genes did not.

"In this study, the question was to define tumor determinants that may predict metastasis," Dr Galon said.

Toward that end, researchers looked at four randomly selected cohorts of 838 patients with CRC, one from the Cancer Genome Atlas and three from the Laennec and Européen Georges Pompidou Hospitals, which included tissue samples and DNA for one of the cohorts.

Genetic profiles were obtained using several protocols, including next-generation sequencing, array comparative genomic hybrization, and Affymetrix arrays. RNA expression was obtained from RNA-Seq expression data and quantitative polymerase chain reaction. Blood and lymphatic vessel density and immune cell populations in tumor and tumor margins were determined from immunohistochemical staining of paraffin-embedded tissue samples using appropriate antibodies.

Patients with CRC were divided into two cohorts, those with no metastases (M0) and those with metastases (M1).

The team found no differences between these patient cohorts for results on cancer driver, cancer pathway-related genes, gene amplification and deletions, and genes associated with tumor metastases (eg, Wnt).

However, mutations in FBXW7 were associated with the absence of metastases and were seen in M0 patients across cohorts. This correlated with increased expression of T-cell proliferation and antigen-presenting functions. Dr Fox said that mutated FBXW7 increases inflammatory signaling, thereby boosting the immune response.

Researchers looked at the tumor microenvironment of M0 and M1 patients and measured the density of blood and lymphatic vessels. They found that only lymphatic vessel density was protective against metastasis. In patients with synchronous or metachronous metastasis, lymphatic blood vessel density was significantly decreased; in M0 patients, lymphatic vessel density was significantly higher.

When they looked at immune cell density, Dr Galon and colleagues found that the tumor centers and invasive margins of patients with M1 metastases had a significantly lower density of T cells associated with adaptive immune responses — CD3 (total T cells), CD4 (T helper cells), MHC class II, CD8 (cytotoxic), TH1, memory, and natural killer cells. In addition, the cytotoxic molecule granzyme B was significantly decreased in M1 patients across cohorts.

"When granzyme B and lymphatic vessels at the invasive margin were high, none of the patients developed metastases," Dr Galon told Medscape Medical News.

"Decreased lymphatic vessel density at the tumor margin and low levels of granzyme B at the center of tumors were both predictive of metastases," he added.

Next, the Immunoscore was calculated by quantifying CD3 and CD8 cells in primary tumors. Immunoscores range from 0 to 1 (I0 to I4). Tumors with low Immunoscores (I0) were overrepresented in M1 patients compared with M0 patients.

When researchers stratified patients on the basis of tumor Immunoscore, patients with a low Immunoscore had shorter survival compared with patients with a high Immunoscore. This was true for both the M0 and M1 patients across cohorts, suggesting that a low Immunoscore in M0 patients is predictive of shorter survival. In analyzing premetastatic pathologic features in M0 patients, the data support the notion that decreased immunity is a cause rather than the consequence of metastases.

"A high Immunoscore, high lymphatic vessel density at the tumor margin, and high granzyme B at the tumor center are all predictive of absence of metastases," Dr Galon said.

Although each tumor has a unique tumor profile, the tumor microenvironment and the Immunoscore are a better prognostic indicator for metastases, with Immunoscore also predicting overall survival, Dr Galon explained.

"This study further supports initial observations made in 2006 that an immune response plays a critical role in determining outcomes of patients," said Dr Fox. "It underscores the importance of the immune response. Patients with an immune response have a low risk of metastases, and as the immune response decreases, metastases increase," he added.

Study in Patients With Brain Metastasis

In the second study, published in the January issue of OncoImmunology, the same research group showed that Immunoscore applied within metastases could predict overall survival in patients with brain metastases.

For the study, the team conducted an analysis of specimens of brain metastases from 116 patients who had a single brain metastasis and were treated with neurosurgical resection.

"We detected tumor infiltrating lymphocytes in 99% of these patients," Dr Galon said.

An Immunoscore was available for 97 patients; 60% had a low Immunoscore, and 40% had a high Immunoscore.

In this study, researchers reported a median survival of 10 months for patients with a low Immunoscore vs 27 months for patients with a high Immunoscore.

"Even in late-stage disease, such as brain metastasis, Immunoscore plays an important role in survival," Dr Galon told Medscape Medical News.

Relevance of Immunoscore to Clinical Practice

"Immunotherapies are currently changing the clinical management across many metastatic stage cancers," Dr Galon said. Immunotherapy works by targeting the T cells, boosting the immune system, and increasing the number of reactive T cells, Dr Galon explained.

"Because a high Immunoscore protects against metastases, our study suggests that immunotherapies should also be beneficial in the clinical management of early-stage disease," he said.

Dr Fox agreed: "This study raises the possibility to use checkpoint blockade earlier." He continued: "However, an objective response requires patients to have good immune responses, and we know from this study that not all patients will have robust anticancer immune responses," he said.

According to Dr Fox, that is likely why patients with CRC have such a low response rate to checkpoint blockade. This study suggests that there is a critical role for cancer vaccines to boost immune responses in patients with a low Immunoscore, he further noted.

"Currently, tumor cell pathology determines risk stratification in colorectal cancer. However, Immunoscore may better stratify patients compared with the currently used TNM classification and should be incorporated into risk stratification," Dr Galon said.

"For example, Immunoscore could be used to stratify patients with colorectal cancer into high-risk and low-risk groups, which could then determine therapeutic choices for patients," he added.

"Based on these data, high-risk groups would be given a vaccine. Dr Chris Heery, at the National Cancer Institute, is already planning such a trial," Dr Fox said

The Immunoscore may also be important for patients with other types of cancer. A phase 2 study for patients with non–small cell lung cancer is evaluating whether a cancer vaccine can induce strong anticancer immunity in patients with a low Immunoscore, a concept that will be critical to improving responses to checkpoint blockade alone.

Medscape Medical News discussed the future of Immunoscore with Vincent Fert, president and CEO of HalioDx, a company seeking to commercialize the tool.

Regarding the question of why Immunoscore has not been more widely adopted, given the fact that the concept has been known for some time, Fert replied, "While it is a promising concept, it was not ready for clinical practice." Previously, the concept was explored in research studies. Now HalioDx has successfully completed the research, feasibility, and industrialization stages of Immunoscore, and it is now in its final development phase.

"Immunoscore should be available to centers and hospitals treating colon cancer across Europe in June 2016," Fert said. "Discussions with the United States Food and Drug Administration have been initiated; however, this technology will not be commercially available in the US until 2017-2018," he added.

Fert indicated that studies are underway to demonstrate the value of Immunoscore in stage II and stage III colon cancer and its utility as a predictive marker for response to chemotherapy in stage III disease. Currently, HalioDx is the only company that is set to commercialize the use of Immunoscore.

Dr Galon and Vincent Fert are cofounders of HalioDX SAS, which is commercializing the HalioDx tests. Dr Fox is a cofounder and CEO of UbiVac, which has cancer vaccines in clinical trials.

Sci Transl Med. Published online February 25, 2016. Abstract

Oncoimmunology. Published online June 9, 2015. Abstract

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