Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade

Martínez, Carlos A.; Kang, Wenjun; Chen, Meng-Jie; Zha, Yuanyuan; Hseu, Robyn D.; Gutiontov, Stanley I.; Turchan, William Tyler; Lynch, Connor; Pointer, Kelli B.; Chang, Paul; Murgu, Septimiu; Husain, Aliya N.; Cody, Brittany; Vokes, Everett E.; Bestvina, Christine M.; Patel, Jyoti D.; Diehn, Maximilian; Gajewski, Thomas F.; Weichselbaum, Ralph R.; Chmura, Steven J.; Pitroda, Sean P.

doi:10.1038/s43018-022-00467-x

Cited by 36 publications

(24 citation statements)

References 52 publications

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“…This explains the large number of CD4 and CD8 T cells and CD68 macrophages in ltrating the myocardium and cardiac conduction system by biopsy in fulminant myocarditis [4]. Spurr have found that local ablative radiotherapy stimulated the immune response [14].…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and prognostic impact of immune checkpoint inhibitor-associated myocarditis in advanced non-small cell lung cancer

Sun

et al. 2023

Preprint

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Background: Myocarditis is a rare immune-related adverse events (irAEs) with high mortality rates, with few reports on its clinical characteristics and prognostic impact. This study designed to explore the associations between cardiac parameters and outcomes of myocarditis in advanced non-small cell lung cancer (NSCLC) who treated with immune checkpoint inhibitor (ICI). Methods: Fourteen patients diagnosed with ICI-associated myocarditis by clinicians were admitted to the study analysis. By Cox univariate and multivariate survival analyses, potential risk factors for the development of severe myocarditis were identified. Survival analysis was also performed to explore the prognosis of patients with myocarditis. Results: Among patients with myocarditis, higher B-type natriuretic peptide (BNP) levels (P=0.04) and conduction block (P=0.03) were associated with progression to severe myocarditis.In addition, high lactate dehydrogenase (LHD)levels (P=0.04) and myocarditis onset within 2 months (P=0.02) were prognostic factors of severe myocarditis. The median progression-free survival (PFS) time and median overall survival (OS) time for all patients were 5.9 months and 18.5 months, respectively. However, there were no statistical differences between mild and severe cohorts in terms of PFS and OS (PFS: 4.5 vs. 8.5 months, P=0.17; OS: 21.3 vs. 18.5months, P=0.36). And we found that the earlier occurrence of myocarditis, worse PFS prognosis (4.5 months vs. 10.5 months, P=0.008), while no difference in OS (18.5 months vs. 21.3 months, P=0.35). Conclusion: Compared to mild myocarditis, severe myocarditis presented with higher BNP levels and cardiac conduction abnormalities. In addition, patients with mild and early myocarditis tended to have better survival rates.

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Section: Discussionmentioning

confidence: 99%

Clinical characteristics and prognostic impact of immune checkpoint inhibitor-associated myocarditis in advanced non-small cell lung cancer

Sun

et al. 2023

Preprint

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“…Blockade of the immunosuppressive responses may improve radiotherapy or overcome radioresistance [ 269 ]. While there is evidence to suggest that anti-PD1/CTLA4 immune checkpoint inhibitors may enhance both local and distant tumor responses to radiotherapy in preclinical studies and some clinical trials [ 270 , 271 ], the positive interaction between radiotherapy and immune checkpoint blockade is not achieved in many clinical settings [ 272 ]. It warrants further studies to determine how the synergy between radiotherapy and immune checkpoint blockade can be achieved in certain contexts.…”

Section: Activation Of Rlr Signaling By Radiotherapy Chemotherapy And...mentioning

confidence: 99%

“…It warrants further studies to determine how the synergy between radiotherapy and immune checkpoint blockade can be achieved in certain contexts. A recent study indicates that high tumor aneuploidy may be a biomarker for enhanced responsiveness to concurrent radiation and immune checkpoint blockade in patients with non-small cell lung cancer [ 272 ].…”

Section: Activation Of Rlr Signaling By Radiotherapy Chemotherapy And...mentioning

confidence: 99%

“…In contrast, a phase II, nonrandomized study indicates promising antitumor activity of pembrolizumab in combination with concurrent chemoradiation therapy in patients with treatment-naïve, locally advanced, stage III non-small cell lung cancer [ 319 ]. The identification of predictive biomarkers and the timing of radiotherapy and immune checkpoint blockade may be important to allow a subset of cancer patients to benefit from combination therapy [ 272 ].…”

Section: Clinical Testing Of Cancer Therapy Involving Rlrs Activationmentioning

confidence: 99%

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Exploiting RIG-I-like receptor pathway for cancer immunotherapy

et al. 2023

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RIG-I-like receptors (RLRs) are intracellular pattern recognition receptors that detect viral or bacterial infection and induce host innate immune responses. The RLRs family comprises retinoic acid-inducible gene 1 (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) that have distinctive features. These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize “immune-cold” tumors to immune checkpoint blockade. In this review, we summarize the current knowledge of RLRs signaling and discuss the rationale for therapeutic targeting RLRs in cancer. We describe how RLRs can be activated by synthetic RNA, oncolytic viruses, viral mimicry and radio-chemotherapy, and how the RNA agonists of RLRs can be systemically delivered in vivo. The integration of RLRs agonism with RNA interference or CAR-T cells provides new dimensions that complement cancer immunotherapy. Moreover, we update the progress of recent clinical trials for cancer therapy involving RLRs activation and immune modulation. Further studies of the mechanisms underlying RLRs signaling will shed new light on the development of cancer therapeutics. Manipulation of RLRs signaling represents an opportunity for clinically relevant cancer therapy. Addressing the challenges in this field will help develop future generations of cancer immunotherapy.

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“…Tumor mutational burden has been established as a biomarker predicting immunotherapy response of tumors when TMB itself is high, but there is a big portion of cancer patients whose tumors do not fall in this category and who could potentially benefit from complementary predictor tools. In this regard, a recent study has reported that high tumor aneuploidy provides improved responses to combined immune checkpoint blockade and radiation therapy in non-small cell lung cancer (Spurr et al 2022a ). Further investigation is required to determine the mechanisms that may promote or suppress immunotherapy responses in the context of aneuploid or CIN tumors, and the value of measuring aneuploidy and/or FGA/CIN as biomarkers of therapy response in bigger patient sample sizes and across tumor types.…”

Section: Therapeutic Opportunities To Exploit Cin Adaptation In Cancermentioning

confidence: 99%

Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

Dhital

Rodríguez-Bravo

2023

Chromosome Res

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Chromosomal instability (CIN) is a pervasive feature of human cancers involved in tumor initiation and progression and which is found elevated in metastatic stages. CIN can provide survival and adaptation advantages to human cancers. However, too much of a good thing may come at a high cost for tumor cells as excessive degree of CIN-induced chromosomal aberrations can be detrimental for cancer cell survival and proliferation. Thus, aggressive tumors adapt to cope with ongoing CIN and most likely develop unique susceptibilities that can be their Achilles’ heel. Determining the differences between the tumor-promoting and tumor-suppressing effects of CIN at the molecular level has become one of the most exciting and challenging aspects in cancer biology. In this review, we summarized the state of knowledge regarding the mechanisms reported to contribute to the adaptation and perpetuation of aggressive tumor cells carrying CIN. The use of genomics, molecular biology, and imaging techniques is significantly enhancing the understanding of the intricate mechanisms involved in the generation of and adaptation to CIN in experimental models and patients, which were not possible to observe decades ago. The current and future research opportunities provided by these advanced techniques will facilitate the repositioning of CIN exploitation as a feasible therapeutic opportunity and valuable biomarker for several types of human cancers.

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Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade

Cited by 36 publications

References 52 publications

Clinical characteristics and prognostic impact of immune checkpoint inhibitor-associated myocarditis in advanced non-small cell lung cancer

Clinical characteristics and prognostic impact of immune checkpoint inhibitor-associated myocarditis in advanced non-small cell lung cancer

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

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