A Sampling of Highlights from the Literature

A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments

NKs calling in the DCs (by Penn1234567, based on L. Kohidai image, via Wikimedia Commons)

Stimulatory DCs are pivotal in shaping immune responses to tumors. These cells are recruited to the melanoma tumor microenvironment by NK cell–secreted Flt3L, which promotes production of stimulatory DCs. NK cells form synapse-like engagements with DCs that, in turn, increase DC survival. The frequency of these cell types correlates with anti–PD-1 responsiveness.

Barry KC, …, Krummel MF. Nat Med 2018 Jun 25. DOI: 10.1038/s41591-018-0085-8.

Two mechanisms by which tumors encourage immunosuppressive microenvironments

Controlling the tumor microenvironment (by skeeze via Pixabay)

By comparing tumor cell clones derived from different cells of a pancreatic ductal adenocarcinoma, Li and colleagues find that only some tumors formed from such clones acquire infiltrating T cells, whereas others that produce CXCL1 suppress infiltration. Mixing tumor cell clones that support infiltration with those that do not showed the dominance of suppressive clones. Alonso and colleagues examine recognition of tumor neoantigens in a genetically driven mouse tumor model of lung adenocarcinoma and find that naïve CD4⁺ T cells are primed in the draining lymph nodes but, rather than become effector cells, either become anergic or are induced to become peripheral Tregs. Thus, tumors appear to promote conditions that recapitulate the mechanisms responsible for peripheral self-tolerance.

Li J, …, Stanger BZ. Immunity 2018 Jun 26. DOI: 10.1016/j.immuni.2018.06.006.

Alonso R, …, Lantz O. Nat Commun 2018 May 29. DOI: 10.1038/s41467-018-04524-x.

Interfaces of malignant and immunologic clonal dynamics in ovarian cancer

Selection and survival (by Elembis via Wikimedia Commons)

Tumor cell diversity can result from cancer immunoediting. Multiple peritoneal sites from 38 patients with high-grade serous ovarian cancer were assessed for immunologic features that affect tumor cell diversity. Tumor-infiltrating immune cells select for tumor cell clones that then escape immune detection, which can result in spread of tumors lacking infiltrates and resistant to immunotherapy.

Zhang AW, …, Shah SP. Cell 2018 Jun 14;173:1755–1769.e22.

Nonconventional inhibitory CD4⁺Foxp3⁻PD-1^hi T cells as a biomarker of immune checkpoint blockade activity

PD-1 blockade could help drain inhibitory subset accumulation (by Semevent via Pixabay)

CD4⁺Foxp3⁻ cells with high expression of PD-1 accumulate in the tumors of patients with melanoma and non–small cell lung cancer, where they inhibit antitumor responses in a PD-1/PD-L1–dependent manner. This inhibitory CD4⁺ population has follicular helper T cell–like characteristics. CTLA-4 blockade enhances accumulation of these cells, which interferes with antitumor responses, and the accumulation can potentially be abrogated by concurrent PD-1 blockade.

Zappasodi R, …, Wolchok JD. Cancer Cell 2018 Jun 11;33:1017–1032.e7.

The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy

Surgery-induced tumor outgrowth linked to wound-healing response (by L. Moreno, David Grant USAF Medical Center)

Early recurrence of breast cancer after surgical resection is not uncommon, raising questions if surgical tumor disruption induces spread or promotes outgrowth of dormant tumors. Using a novel orthotopic mouse model, outgrowth is now linked directly to the surgery-induced, wound-healing inflammatory response. Dormancy is maintained by T cells, and the increase in tumor outgrowth accompanying surgery could be combated with anti-inflammatories. Thus, surgery has systemic effects that can interfere with antitumor responses and promote tumor outgrowth.

Krall JA, …, Weinberg RA. Sci Transl Med 2018 Apr 11;10: eaan3464.

CD8⁺ T cell subsets that have prognostic value for solid tumors

Identifying new antitumor cells (by ho7dog via Pixnio)

CD8⁺ T cells are crucial for antitumor activity. Thommen and colleagues found that a subset of CD8⁺ T cells expressing high amounts of PD-1 are functionally and transcriptionally distinctive. These cells, which accumulate in non–small cell lung cancer, predict survival and strong antitumor responses in patients treated with anti–PD-1. Using single-cell RNAseq, Savas and colleagues identified a population of tissue-resident memory-like CD103⁺CD8⁺ T cells that highly express checkpoint proteins amidst breast cancer–infiltrating T cells. These cells correlated significantly with a better prognosis for patients with triple-negative breast cancer, making the cells targets for modulation.

Thommen DS, …, Zippelius A. Nat Med 2018 Jun 11. DOI: 10.1038/s41591-018-0057-z.

Savas P, …, Loi S. Nat Med 2018 Jun 25. DOI: 10.1038/s41591-018-0078-7.