Revealing the Tumor Microenvironment’s Vulnerabilities

NGS sequencing technologies used in multiomic approaches are showing how immunotherapies can overcome the tumor ecosystem’s intricate defenses

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As treacherous as it is complex, the tumor microenvironment (TME) is composed of different cell types that produce an abundance of cross-talking molecules, extracellular vesicles, and metabolites. All of these components work together to disrupt immunosurveillance and thwart the immune response.1–3 Altogether, the TME can support tumor growth and metastatic dissemination.

To undercut the TME, scientists must look into the intricacies to identify the interactions that support the TME’s existence. Once this is accomplished—through multiomic profiling technologies—it will be possible to develop increasingly powerful cancer therapies, including immunotherapies that will be the disease’s undoing.

Darwinian evolution gone awry

“Cancer is essentially a case of Darwinian evolution gone awry,” says Robert Yamulla, PhD, cancer research segment manager at Illumina. “A tumor does not consist of one cell type. Rather, it is an ecosystem of many distinct, interacting cell populations that differ in mutational profiles and cellular identity. And, as per the principles of Darwinian evolution, cells that are best suited to the microenvironment survive and multiply.”

Myriad cell types populate and influence the TME—tumor cells, a full repertoire of immune cells, and stromal cells such as pericytes, fibroblasts, adipocytes, and endothelial cells, as well as bacteria and fungi. Each cell type is important and contributes uniquely to fundamental cancer biology and translational research.4

“Tumor-associated myeloid cells—which mainly consist of macrophages—affect antitumor T-cell responses, and the abundance of macrophages in solid tumors often correlates with poor prognosis in patients,” explains Kelly Kersten, PhD, a postdoctoral fellow at the University of California, San Francisco. “We have recently found that macrophages and exhausted T cells in the tumor microenvironment are co-dependent in a spatial manner.5 We are targeting these interactions to reinvigorate antitumor T-cell responses to improve treatment strategies.”

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Diversity of cell types within the cancer microenvironment

Complexity multiplied

To add to the conundrum, not all cancer cells in a TME are similar. In a recent study of 83 spatial samples from 31 patients with pancreatic ductal adenocarcinoma, researchers based at Washington University in St. Louis identified tumor and transitional subpopulations with distinct histological features and different drivers. The findings indicated that each cell population plays a unique role in tumor biology.6

“Tumor heterogeneity is not restricted to cancer cells,” Yamulla observes. “Noncancerous cell types within the TME such as fibroblasts and immune cells and even microbial populations significantly influence tumor biology.”

Indeed, as pointed out in a recent article in Nature, scientists are “exploring the role of diet and gut-microbe diversity, as well as revealing interactions between the organisms that reside in the gut and those that live in tumors themselves, potentially opening up new targets for treatment.”7

Whether fungi act similarly is unknown, motivating characterizations of the pan-cancer mycobiome. A study conducted by researchers based at Weizmann Institute of Science found strong positive correlations between fungal and bacterial diversities, abundances, and co-occurrences across several cancer types. The findings suggest that TMEs may allow for multidomain microbial colonization, opening up yet another area for potential stratification and treatment protocols.8

Therapeutic implications

“Changes to the microenvironment due to introduction of novel stressors like therapies may select for certain subpopulations of cancer cells,” Yamulla says. “The subpopulations that become dominant may not be the ones that were dominant at the time therapy commenced. But even so, their unique genotype may result in a cell survival advantage, which contributes to disease recurrence.”

Unfortunately, immunotherapies often fail, which is why the TME’s entirety must be considered when designing new immunotherapies and combination protocols.

Multiomic approaches

These outcomes clearly demonstrate the need to cast a wider net to include microbes and single-cell analysis to further map the TME’s complexity and interactions. In fact, a study by the Melanoma Institute of Australia points out that heterogeneity is the barrier to identifying patients who will be resistant to treatment.9 Multiomic approaches are a clear path to better capture complexity by measuring cause and consequence of complex phenotypes.


4. Labani-Motlagh A, Ashja-Mahdavi M, Loskog A. The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses. Front. Immunol. 2020; 11: 940. DOI: 10.3389/fimmu.2020.00940.
5. Kersten K, Hu KH, Combes AJ, et al. Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer. Cancer Cell 2022; 13; 40(6): 624-638.e9. DOI: 10.1016/j.ccell.2022.05.004.
6. Cui Zhou D, Jayasinghe RG, Chen S, et al. Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer. Nat. Genet. 2022; 54(9): 1390–1405. DOI: 10.1038/s41588-022-01157-1.
7. Erdmann J. How gut bacteria could boost cancer treatments. Nature 2022; 607: 436–439. DOI: 10.1038/d41586-022-01959-7.
8. Narunsky-Haziza L, Sepich-Poore GD, Livyatan I, et al. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell 2022; 185(20): 3789–3806.e17. DOI: 10.1016/j.cell.2022.09.005.
9. Newell F, Pires da Silva I, Johansson PA, et al. Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance. Cancer Cell 2022;40(1):88-102.e7. DOI: 10.1016/j.ccell.2021.11.012.


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