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Lung Cancer Immune Microenvironment May Vary Within Tumor, Complicating TMB-Based Predictions

NEW YORK (GenomeWeb) – New research suggests that a single biopsy may not be sufficient for profiling immune cell activity in the microenvironment of non-small cell lung carcinoma (NSCLC) tumors. 

Researchers from China and the US used exome sequencing, RNA sequencing, and T-cell receptor repertoire sequencing, in combination with immune cell infiltration profiling and a machine learning algorithm, to characterize primary tumor and anti-tumor immune microenvironment features in samples from 15 individuals with recently diagnosed, surgically-treated NSCLC. Their results, published online today in Nature Communications, suggest that immune activity can vary dramatically within the microenvironment of the same tumor.

The work suggests "the accurate identification of candidates for immunotherapy might be improved by more comprehensively measuring local tumor attributes, in comparison to solely focusing on [tumor mutational burden] or neoantigen load as is the current practice," co-corresponding authors Bo Zhu, a cancer researcher at Third Military Medical University and Chongqing Key Laboratory of Tumor Immunotherapy, and Qi-Jing Li, an immunology researcher affiliated with Duke University and the Third Military Medical University, and their co-authors wrote.

With the promising results observed for some NSCLC patients treated with immune checkpoint therapies, such as the anti-PD-1 drug nivolumab, the team explained, investigators have been searching for tumor or tumor microenvironment features associated with immunotherapy success.

In line with this, the authors set out to use several complementary approaches to "assess immunogenicity beyond neoantigen abundance and mutational burden."

"Since spatially heterogeneous immunoreactivity might weaken the predictive value of current biomarkers," they wrote, "we also sample multiple regions from each individual NSCLC tumor."

Specifically, the researchers performed exome and T-cell receptor beta-chain repertoire sequencing on 57 samples from 15 NSCLC patients, integrating RNA-seq data on 44 samples from 12 of the patients in their subsequent tumor and peripheral blood mononuclear cell analysis.

On the somatic mutation side, the team identified almost 2,500 non-synonymous mutations, with two to more than 380 mutations turning up in each of the tumor loci tested. These alterations may contribute to the formation of neoantigens that could alert immune cells to the tumor's existence.

When the researchers considered the interactions between immune features and such mutations, they found that tumor mutational burden corresponded to local T-cell clonal populations. However, local cytotoxic, infiltrating T-lymphocyte immune cell features did not seem to coincide with neoantigen levels.

Overall, the authors reported, "we found that the tumor immunogenicity cannot be directly predicted by either local mutation burden or neoantigen loads: tumor loci with high [tumor mutational burden] can be found in the cold area and loci with low [tumor mutational burden] can be categorized as immunologically hot tissues."

The team's integrated analyses on dozens of infiltrating or regulatory T-cell sub-populations also pointed to widespread differences in microenvironment immune features from distinct sites in and around the same NSCLC tumors, with intra-tumor heterogeneity reaching or exceeding the levels of heterogeneity found from one patient to the next.

"[T]his study cautions against the use of overly simplified immune-monitoring strategies to guide immune therapies," the authors concluded. "It suggests that multi-parameter and multi-locus analysis will aid efforts to assess the territorial and heterogeneous features of immune niches within tumors, resulting in the development of more precise and personalized immune therapies to treat cancers."