Highlights from Recent Cancer Literature

Despite hundreds of trials examining the combination of radiotherapy with immunotherapy, evidence for synergy as well as predictive biomarkers are lacking. Spurr and colleagues conducted a trial to examine the efficacy of the combination of immunotherapy plus multisite ablative radiotherapy in non-small cell lung cancer patients. Genomic and transcriptomic analyses of baseline and on-treatment biopsies demonstrated that concurrent radiation and immunotherapy increased the adaptative immune response while radiation alone decreased this response. Furthermore, high baseline aneuploidy predicted improved outcomes in patients treated with concurrent therapy.

Expert Commentary: This study suggests that high tumor aneuploidy may be a biomarker of response to concurrent radiotherapy and immunotherapy and should be validated in future trials.

Spurr LF, Martinez CA, Kang W, Chen M, Zha Y, Hseu R, et al. Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade. Nat Cancer 2022;3:1498–512.

The potential impact of artificial intelligence in pathological evaluation has rarely been tested on large clinical datasets. Using standard immunostaining on tissue microarrays representing over 1000 patients, Foersch and colleagues leveraged artificial intelligence to construct a prognostic classification tool (AImmunoscore) for colorectal cancer. AImmunoscore used staining data for multiple markers to predict outcome more accurately than models that used single stains, or statistical machine learning approaches alone. A test case in rectal cancer suggests applicability to other gastrointestinal cancers.

Expert Commentary: Though the first implementation focuses on a cancer type where immune cell composition is known to have predictive value, this approach could potentially be deployed broadly to cancers with few prior prognostic indicators.

Foersch S, Glasner C, Woerl AC, Eckstein M, Wagner DC, Schulz S, et al. Multistain deep learning for prediction of prognosis and therapy response in colorectal cancer. Nature Medicine; Published online January 9, 2023; doi: 10.1038/s41591-022-02134-1.

Immunoediting is a multistep process during tumorigenesis that can ultimately result in the emergence of immune-resistant tumor clones. While exploring links between immunoediting and tumor metabolism, Tsai and colleagues showed that, in shifting from oxidative phosphorylation to aerobic glycolysis, tumor cells escaped from T-cell–mediated immunity. In melanoma and hepatocellular carcinomas, the authors showed that tumor development in immunocompetent mice, compared with T/B cell-deficient Rag knockout mice, drove conversion from metabolism utilizing the TCA cycle to glycolysis. This metabolic switch was dependent on T cells and IFNγ, and IFNγ activated an alternative STAT3-mediated pathway to increase c-Myc expression. c-Myc induction was sufficient to mediate T-cell escape. Metabolic genes regulated by c-Myc promoted immune escape and were also found altered in human cancers.

Expert Commentary: Altered metabolic programming in cancer cells driven by an IFNγ-STAT3-c-Myc axis promotes tumor escape from T-cell responses.

Tsai CH, Chuang YM, Li X, Yu YR, Tzeng SF, Teoh ST, et al.  Immunoediting instructs tumor metabolic reprogramming to support immune evasion. Cell Metab 2023;35:118-133.e7.

In prostate cancer, roles for the noncanonical WNT, WNT5a, are confounding. Elevated WNT5a associates with progression to metastatic castration-resistant prostate cancer (mCRPC), while also correlating with improved prognosis in localized prostate cancer. The present study by Wang and colleagues indicates that WNT5a or a WNT5a mimetic peptide markedly inhibited prostate cancer organoid growth in vitro and tumor growth in vivo. Growth suppressive effects of WNT5a were mediated by ROR2-dependent activation of the Hippo pathway to repress YAP1 activity. Interestingly, the authors observed a progressive decline in ROR2 mRNA expression from benign prostate to localized prostate cancer and to mCRPC. Lower ROR2 was associated with decreased disease-free and overall survival in The Cancer Genome Atlas prostate cancer cases.

Expert Commentary: WNT5a signaling through ROR2 activates the Hippo pathway to downregulate YAP/TAZ activity and to suppress tumor growth. ROR2 provides a potential biomarker to identify patients that could benefit from WNT5a inhibition.

Wang K, Ma F, Arai S, Wang Y, Varkaris A, Poluben L, et al. WNT5a signaling through ROR2 activates the Hippo pathway to suppress YAP1 activity and tumor growth. Cancer Research; Published OnlineFirst January 9, 2023; doi: 10.1158/0008-5472.CAN-22-3003.

Serine/threonine kinases (ser/thr) are critical regulators of tumorigenesis through their ability to act on numerous pathways in the cell and have become attractive targets for therapy. Johnson and colleagues used peptide scanning to catalog the substrate specificity of 303 ser/thr kinases. Substrate motif analysis revealed absent amino acids to mediate negative selection of the substrate that drove substrate specificity. Additionally, this work showed that kinases with different sequences/positions on the evolutionary phylogenetic tree converged based on target substrate motifs. Thus, distantly related kinases can phosphorylate the same substrate motifs. This new analysis has reorganized the ser/thr kinome into at least 38 motif classes and introduced several shared motif features. Overall, the linear sequence context of phosphorylation sites contributes substantially to kinase-substrate relationships.

Expert Commentary: This work provides important biological insight for human biology and cancer research and kinase targeting as treatment strategies.

Johnson JL, Yaron MY, Huntsman EM, Kerelsky A, Song J, Regev A, et al. An atlas of substrate specificities for the human serine/threonine kinome. Nature 2023;613:759–66.

Modification of mRNAs by N⁶-methyladenosine (m⁶A) has been demonstrated to be important for tumor progression in many different contexts to date. Han and colleagues performed a CRISPR screen and identified the mRNA modification m⁶A methyltransferase 16 (METTL16) as essential in acute myeloid leukemia (AML) cells. In vivo, murine bone marrow lineage negative progenitor (BM-Lin⁻) hematopoietic stem cells formed AML when transduced with an MLL-AF9 fusion gene. Cre-mediated excision of METTL16 blocked this AML. Functionally, METTL16 loss impaired leukemia stem cell renewal and proliferation. Branched chain amino acid transaminases 1 and 2 (BCAT1 and BCAT2) were top targets regulated by METTL16. Loss of METTL16 could be rescued with forced re-expression of BCAT1.

Expert Commentary: Epitranscriptomics and m⁶A RNA modifications are critical regulators of cancer growth, with METTL16 acting as an essential vulnerability in AML.

Han L, Dong L, Leung K, Zhao Z, Li Y, Gao L, et al. METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism. Cell Stem Cell 2023;30:52–68.e13. doi: 10.1016/j.stem.2022.12.006.

Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.