Two groups of researchers have generated the first comprehensive “immune atlases” of clear cell renal cell carcinoma and early lung adenocarcinoma. Their work better illuminates the tumor immune microenvironment and may lead to more effective immunotherapy strategies.

Researchers from the University of Zurich in Switzerland and Mount Sinai School of Medicine in New York, NY, have generated the first comprehensive “immune atlases” of clear cell renal cell carcinoma (ccRCC) and early lung adenocarcinoma, respectively. Their simultaneously published work better illuminates the tumor immune microenvironment and may lead to more effective immunotherapy strategies.

Both groups used mass cytometry—which enables rapid, fine-grained scrutiny of millions of single cells—along with transcriptome analyses and multiplex tissue imaging to create their atlases.

Bernd Bodenmiller, PhD, senior author of the ccRCC study, and his team analyzed tumor samples from 73 patients and described a picture of immunosuppression in T cells (Cell 2017;169:736–49). PD-1 was broadly expressed, but the levels of other inhibitory receptors, such as TIM3 and CTLA4, fluctuated far more, with varying combinations observed both within and among patients. As well, they pinpointed CD38 as a new marker of T-cell exhaustion in ccRCC. “It's potentially another checkpoint that could be blocked to relieve immunosuppression,” he says.

The researchers also identified 17 functionally diverse subsets of tumor-associated macrophages (TAM) in their samples. Where certain TAMs were present, others were absent, Bodenmiller notes—for instance, the M-5, M-11, and M-13 TAM subsets were largely mutually exclusive.

“A tumor's immune landscape is not random; it has structure,” he adds. The composition of this landscape appears to correlate with progression-free survival, which the team found to be shorter in patients with high frequencies of M-11 or M-13 TAMs, and low frequencies of M-5. Bodenmiller cautions, though, that “this is a statistical relationship we found, and just one of many that a larger study would likely uncover. Follow-up experiments are needed to reveal the underlying biology.”

Miriam Merad, MD, PhD, director of Mount Sinai's Precision Immunology Institute, and her team analyzed tumor samples from 28 patients with early or late-stage lung adenocarcinoma to create their immune atlas (Cell 2017;169:750–65). They reported a strong signature of immunosuppression early on in this disease: Stage I lesions lacked natural killer cells but were rich in regulatory T cells expressing CTLA4, ICOS, and other inhibitory receptors, as well as exhausted PD-1–expressing CD8+ T cells.

Early lung adenocarcinomas also lacked CD141+ dendritic cells; previously, Merad showed that this subset's counterpart in mice—CD103+ dendritic cells—is necessary for enhanced responses to PD-L1 blockade (Immunity 2016;44:924–38). In addition, the tumors had an abundance of macrophages expressing PPARγ, a transcription factor that drives an immunosuppressive program.

Turning their attention to late-stage lesions, the team observed a very similar immune profile—essentially, all the immune changes they found were already present in stage I tumors.

“Our findings indicate that for lung adenocarcinoma, starting immunomodulatory regimens as soon as possible—not waiting until relapse occurs—is important and could be highly beneficial to patients,” Merad says. Earlier diagnosis of lung cancer is becoming more common, she notes, thanks to widespread implementation of low-dose CT screening programs in at-risk populations.

Merad and Bodenmiller agree that beyond targeting PD-1/PD-L1 on T cells, researchers in the immuno-oncology field should develop strategies to reverse dysregulation in myeloid cells, including macrophages and dendritic cells. This would help mitigate a tumor's generally immunosuppressive milieu and prime more robust responses to checkpoint blockade.

To John Wherry, PhD, codirector of the University of Pennsylvania's Parker Institute for Cancer Immunotherapy in Philadelphia, the studies represent “the cutting edge of understanding, at the systems level, immune involvement in cancer.” High-content data analyses, including mass cytometry, are revealing patterns of interaction among diverse cell types in tumor tissue, which were previously difficult to discern, he says.

“Our challenge now is to translate this information into therapies that can target the most central nodes of immune dysregulation in tumors,” Wherry adds. –Alissa Poh

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