Strong vaccine responses during chemotherapy are associated with prolonged cancer survival

Melief, Cornelis J.M.; Welters, Marij J.P.; Vergote, Ignace; Kroep, Judith R.; Kenter, Gemma G.; Ottevanger, Petronella B.; Tjalma, Wiebren A.A.; Denys, Hannelore; Poelgeest, Mariëtte I.E. van; Nijman, Hans W.; Reyners, Anna K.L.; Velu, Thierry; Goffin, Frédéric; Lalisang, Roy I.; Loof, Nikki M.; Boekestijn, Sanne; Krebber, Willem Jan; Hooftman, Leon; Visscher, Sonja; Blumenstein, Brent A.; Stead, Richard B.; Gerritsen, Winald R.; Burg, Sjoerd H. van der

doi:10.1126/scitranslmed.aaz8235

Cited by 91 publications

(103 citation statements)

References 72 publications

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“…43 Potentially, this is a reflection of the suppressive effect of IL-6 on MHC class II, costimulatory molecules and IL-12 production 44 39,45,46 In addition, its contribution to therapy resistance is in line with our data showing the increased systemic and local presence of immature myeloid cells suppressed tumor-specific T-cell reactivity and functions as a vaccine resistance mechanism in mice and patients with progressively growing HPV16 + tumors. 28,47 Finally, our data extend prior observations that upregulation of IL-6 by tumor or increased level of this cytokine in the serum negatively correlates with the induced antitumor response and tumor regression, proposing this cytokine as a predictive biomarker. 48,49 In addition, our data clearly demonstrated the negative effect of IL-6 on myeloid cells in both immunotherapy and chemotherapy settings.…”

Section: Increasing the Strength Of The Initial Tumoricidal Hit Decsupporting

confidence: 86%

Interleukin‐6‐mediated resistance to immunotherapy is linked to impaired myeloid cell function

Nejad

Labrie

Sluis

et al. 2020

Intl Journal of Cancer

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High serum levels of interleukin-6 (IL-6) correlate with poor prognosis and chemotherapy resistance in several cancers. The underlying mechanisms and its effects on immunotherapy are largely unknown. To address this, we developed a human papillomavirus type 16 (HPV16)-associated tumor model expressing IL-6 to investigate the impact of tumorexpressed IL-6 during cisplatin chemotherapy and HPV16 synthetic long peptide vaccination as immunotherapy. The effects of tumor-produced IL-6 on tumor growth, survival and the tumor microenvironment were analyzed. Our data demonstrated that tumor-produced IL-6 conferred resistance to cisplatin and therapeutic vaccination. This was not caused by a changed in vitro or in vivo growth rate of tumor cells, or a changed sensitivity of tumor cells to chemotherapy or T-cell-mediated killing. Furthermore, no overt differences in the frequencies of tumor-infiltrating subsets of T cells or CD11b + myeloid cells were observed. IL-6, however, affected the systemic and local function of myeloid cells, reflected by a strong reduction of major histocompatibility complex (MHC) class II expression on all major myeloid cell subtypes. Resistance to both therapies was associated with a changed intratumoral influx of MHC class II + myeloid cells toward myeloid cells with no or lower MHC class II expression. Importantly, while these IL-6-mediated effects provided resistance to the immunotherapy and chemotherapy as single therapies, their combination still successfully mediated tumor control. In conclusion, IL-6-mediated therapy resistance is caused by an extrinsic mechanism involving an impaired function of intratumoral myeloid cells. The fact that resistance can be overcome by combination therapies provides direction to more effective therapies for cancer.

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Section: Increasing the Strength Of The Initial Tumoricidal Hit Decsupporting

confidence: 86%

Interleukin‐6‐mediated resistance to immunotherapy is linked to impaired myeloid cell function

Nejad

Labrie

Sluis

et al. 2020

Intl Journal of Cancer

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“…Despite the many patients with complete responses, the majority of clinically responding patients show partial tumor regressions after immunotherapy. [1][2][3][4][5][6][7] Several primary and acquired resistance mechanisms, including low tumorspecific antigen load, antigen processing and presentation defects, T-cell exclusion, and local immune suppression by suppressive myeloid cell populations, regulatory T cells and coinhibitory molecule expression, allow tumors to become therapy resistant, limiting the clinical efficacy of the immunotherapeutic approaches used. 8 The concept of immune editing dictates that a non-curative immune response eventually drives tumor immune escape.…”

Section: Introductionmentioning

confidence: 99%

Lack of myeloid cell infiltration as an acquired resistance strategy to immunotherapy

Nejad

Labrie

Abdulrahman

et al. 2020

J Immunother Cancer

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BackgroundImmunotherapy of cancer is successful but tumor regression often is incomplete and followed by escape. Understanding the mechanisms underlying this acquired resistance will aid the development of more effective treatments.MethodsWe exploited a mouse model where tumor-specific therapeutic vaccination results in tumor regression, followed by local recurrence and resistance. In depth studies on systemic, local and tumor intrinsic changes were performed with flow and mass cytometry, immunohistochemistry, transcriptomics and several perturbation studies with inhibitors or agonistic antibodies in mice. Main findings were recapitulated in vaccinated patients.ResultsFull tumor regression and cure of tumor-bearing mice is dependent on the magnitude of the vaccine-induced T-cell response. Recurrence of tumors did not involve classical immune escape mechanisms, such as antigen-presentation alterations, immune checkpoint expression, resistance to killing or local immune suppression. However, the recurrent tumors displayed a changed transcriptome with alterations in p53, tumor necrosis factor-α and transforming growth factor-β signaling pathways and they became immunologically cold. Remarkably, ex vivo cell-sorted recurrent tumors, directly reinjected in naïve hosts retained their resistance to vaccination despite a strong infiltration with tumor-specific CD8+ T cells, similar to that of vaccine-responsive tumors. The influx of inflammatory mature myeloid effector cells in the resistant tumors, however, was impaired and this turned out to be the underlying mechanisms as restoration of inflammatory myeloid cell infiltration reinstated the sensitivity of these refractory tumors to vaccination. Notably, impaired myeloid cell infiltration after vaccination was also associated with vaccine resistance in patients.ConclusionAn immunotherapy-induced disability of tumor cells to attract innate myeloid effector cells formed a major mechanism underlying immune escape and acquired resistance. These data not only stresses the importance of myeloid effector cells during immunotherapy but also demands for new studies to harness their tumoricidal activities.

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“…Therapeutic vaccines can induce durable regressions of premalignant oncogenic human papilloma virus type 16-induced anogenital lesions [101]. To the best of our knowledge, this vaccine containing viral peptides remains the sole therapeutic TSA-based vaccine that has shown reliable efficacy.…”

Section: Discussionmentioning

confidence: 99%

The Origin and Immune Recognition of Tumor-Specific Antigens

Apavaloaei

Hardy

Thibault

et al. 2020

Cancers

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The dominant paradigm holds that spontaneous and therapeutically induced anti-tumor responses are mediated mainly by CD8 T cells and directed against tumor-specific antigens (TSAs). The presence of specific TSAs on cancer cells can only be proven by mass spectrometry analyses. Bioinformatic predictions and reverse immunology studies cannot provide this type of conclusive evidence. Most TSAs are coded by unmutated non-canonical transcripts that arise from cancer-specific epigenetic and splicing aberrations. When searching for TSAs, it is therefore important to perform mass spectrometry analyses that interrogate not only the canonical reading frame of annotated exome but all reading frames of the entire translatome. The majority of aberrantly expressed TSAs (aeTSAs) derive from unstable short-lived proteins that are good substrates for direct major histocompatibility complex (MHC) I presentation but poor substrates for cross-presentation. This is an important caveat, because cancer cells are poor antigen-presenting cells, and the immune system, therefore, depends on cross-presentation by dendritic cells (DCs) to detect the presence of TSAs. We, therefore, postulate that, in the untreated host, most aeTSAs are undetected by the immune system. We present evidence suggesting that vaccines inducing direct aeTSA presentation by DCs may represent an attractive strategy for cancer treatment.

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Strong vaccine responses during chemotherapy are associated with prolonged cancer survival

Cited by 91 publications

References 72 publications

Interleukin‐6‐mediated resistance to immunotherapy is linked to impaired myeloid cell function

Interleukin‐6‐mediated resistance to immunotherapy is linked to impaired myeloid cell function

Lack of myeloid cell infiltration as an acquired resistance strategy to immunotherapy

The Origin and Immune Recognition of Tumor-Specific Antigens

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