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Some patients with acute lymphoblastic leukemia become resistant to CAR T cells despite leukemia retaining the target antigens. Leukemic cells can acquire reduced expression and signaling from death receptors, leading to resistance to CAR T cytotoxicity. Such persistent leukemic cells induce an exhaustion program in CAR T cells with a genetic profile similar but not identical to exhausted nonengineered T cells. Thus, T-cell dysfunction may result from tumor-intrinsic events.

Singh N, …, Ruella M. Cancer Discov 2020 Apr 1;10:552–67.

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Temozolomide is an FDA-approved chemotherapy for glioblastoma (GBM) that mobilizes myeloid cells, inducing antitumor immune responses, but its efficacy remains limited. Von Roemeling et al. find that combining CD47 blockade with temozolomide improves tumor cell phagocytosis, leading to increased antigen presentation, T-cell priming, and cGAS/STING-dependent antitumor responses. Sarkar et al. find that niacin (vitamin B3) synergizes with temozolomide by improving the anti-GBM efficacy of myeloid cells in an IFNα 14-dependent manner. Thus, myeloid cell manipulations can improve adaptive and innate responses and temozolomide efficacy.

von Roemeling CA, …, Kim BYS. Nat Comm 2020 Mar 20;11:1508.

Sarkar S, …, Yong VW. Sci Transl Med 2020 Apr 1;537:eaay9924.

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Therapeutic vaccination stimulates antitumor responses in HPV16-induced anogenital lesions, yet immune suppressive myeloid cells limit efficacy. Standard-of-care carboplatin and paclitaxel reduces immunosuppressive myeloid cells and improves HPV16 vaccination. Treatment of 77 patients with advanced cervical cancer with the antitumor vaccine ISA101, carboplatin, and paclitaxel decreases the immune-suppressive myeloid cells and increases HPV-specific immune responses that correlate positively with patient survival.

Melief CJM, …, van der Burg SH. Sci Transl Med 2020 Mar 18;12:eaaz8235.

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PD-L1 can be expressed on T cells as well as other immune and somatic cells. Ligation of PD-L1 on CD4+ T cells induces STAT3, which interferes with activation and Th1 polarization. Signaling from PD-L1 on a CD8+ T cell promotes an anergic state and is as self-suppressive as PD-1 signaling. Neighboring T cells that express PD-1 are also suppressed, without PD-L1 expression on tumor cells. Expression of PD-L1 on T cells is also sufficient to promote M2 programs on PD-1 expressing macrophages and repress antitumor responses and tumorigenesis.

Diskin B, …, Miller G. Nat Immunol 2020 Apr 1;21:442–54.

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IFNγ in the tumor microenvironment (TME) can have long-range effects. Hoekstra et al. show that tumor-specific CD8+ T cells set up an IFNγ gradient sensed by distant tumor cells, which can both have antitumor activity and increase PD-L1 on bystander antigen-negative tumor cells. Thibaut et al. demonstrate that when CD8+ T cell–derived IFNγ spreads throughout the TME, distant tumor cells receive prolonged exposure to the cytokine, with antitumor effects sustained via STAT1 activity. These articles highlight how local production of IFNγ has far-reaching effects in the TME.

Hoekstra ME, …, Schumacher TNM. Nat Cancer 2020 Mar 9;1:291–301.

Thibaut R, …, Bousso P. Nat Cancer 2020 Mar 9;1:302–14.

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Immunotherapy efficacy is limited in solid tumors due to a variety of factors. Morrison et al. demonstrate that immune checkpoint therapy–resistant pancreatic tumors can be sensitized to immune checkpoint blockade by combining the treatment with agonostic antibodies to CD40. This combination does not require TLR, STING, or IFNα pathways but relies on activating Batf3+ DCs to generate polyfunctional T cells, changing this immunologically cold tumor into a hot one. The data highlight a potential strategy to treat cold tumors.

Morrison AH, …, Vonderheide RH. Proc Natl Acad Sci U S A 2020 Apr 7;117:8022–31.