Repurposing COVID-19 (and other) mRNA vaccines to boost cancer immunotherapy efficacy: mechanistic insights and future directions

Abstract

A recent study by Grippin et al showed that COVID-19 mRNA-lipid nanoparticle vaccines can be strategically implemented to fundamentally reshape the immunosuppressive tumor microenvironment and boost the efficacy of immune checkpoint inhibitors (ICIs) even in patients bearing cancer types that are usually refractory to ICIs. Mechanistically, innate immunological responses elicited by COVID-19 mRNA vaccine negate multiple tumor-associated immune evasion mechanisms and ultimately enable functionally competent polyclonal antitumor CD8⁺ T responses. As many mRNA vaccines are already, or on the point of being, approved for human use, the translational potential of therapies combining mRNA vaccines with ICIs is unprecedented. Indeed, the strategic repurposing of COVID-19 (and other) mRNA vaccines represents a clinically feasible and immediately translatable approach to potentiate the efficacy of ICI-based cancer immunotherapy.

A recently published study by Grippin et al in Nature¹ reported the beneficial antitumor effects of COVID-19 mRNA vaccines administered before, or in combination with, immune checkpoint inhibitors (ICIs).² Remarkably, data from a large cohort of patients demonstrated that COVID-19 mRNA vaccination within 100 days of ICI initiation produces near doubling of overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and melanoma. In patients with NSCLC, median OS improved from 20.6 to 37.3 months, with 3-year OS increasing from 30.8% to 55.7%. Most provocatively, patients with immunologically “cold” tumors (baseline programmed death-ligand 1 (PD-L1) expression <1%, normally refractory to immunotherapy) demonstrated the most dramatic therapeutic benefit. Collectively, the immune priming effect of COVID-19 mRNA vaccine potentiated desired antitumor effects of ICIs in patients with cancer.¹

The majority of patients with cancer fail to respond to ICIs, and this primary or secondary resistance can be corrected by targeting immunosuppression in the tumor microenvironment (TME). In this context, Grippin et al showed that mRNA-based lipid nanoparticle (LNP) COVID-19 vaccines sensitized tumors to immune checkpoint blockade, thus enhancing the clinical efficacy of ICI.¹ Specifically, COVID-19 mRNA vaccines overturned several immune evasion mechanisms within the TME, thus favoring functionally competent antitumor CD8⁺ T cell responses. In preclinical tumor models, mRNA-LNP injections induced a prompt systemic type I interferon (IFN-I) response, enhanced the percentage of CD80⁺, CD86⁺, PD-L1⁺ activated macrophages and dendritic cells (DCs) in the spleen, and improved the presentation of an experimental tumor-associated antigen (TAA), namely the immunodominant ovalbumin-derived MHC (major histocompatibility complex) Class I-restricted octapeptide SIINFEKL, on antigen-presenting cells in tumor-draining lymph nodes (figure 1).¹ These observations are fully consistent with recent work deconvoluting the interplay of innate and adaptive immunity in mRNA vaccination and ICI responses. Thus, IFN-I-driven activation of DCs and myeloid cells appears central to productive antitumor T cell priming. In patients receiving COVID-19 vaccinations, such a systemic IFN-I response was accompanied by elevated expression of PD-L1 in both immune cells, as exemplified by DCs, and malignant cells, as exemplified by NSCLC and melanoma. Interestingly, as compared with monotherapies, combined administration of mRNA vaccine and ICI was particularly efficient in boosting macrophage and DC maturation and in favoring the expansion of PD-1⁺ effector and effector memory CD8⁺ T cells (figure 1). Of note, CD8⁺ T cell responses induced by the combination of mRNA vaccine plus ICI combination were polyclonal, recognize multiple endogenous TAAs, and led to an expansion of CD8⁺ cells both in spleen and within the TME of formerly immunologically “cold” tumors. Such polyclonal CD8⁺ T cell responses constitute a surrogate biomarker of ICI efficacy.¹

Figure 1. Antitumor mechanisms induced by COVID-19 mRNA vaccines and potentiating the efficacy of ICIs. The therapeutic efficacy of ICIs is dampened in hosts that have tumors lacking an abundant immune infiltrate containing tumor antigen-specific T cells. The administration of COVID-19 mRNA vaccine stimulates the production of IFN-I and other relevant chemokines (eg, CXCL10) and drives the maturation of APCs, in particular dendritic cells. Activated APCs migrate to the draining lymph node and present antigens to interacting T cells, ultimately initiating CD8⁺ T cell activation and proliferation. Administration of the COVID-19 vaccine before ICI enables the activation of antitumor CD8⁺ T cells in the TME and tdLN. Effector PD-1⁺ CD8⁺ T cells migrate to tumors, get boosted by ICI targeting the PD-1 axis, and perform enhanced cytotoxic functions against cancer cells at local and metastatic sites. APCs, antigen presenting cells; CXCL10, C-X-C motif chemokine ligand 10; DCs, dendritic cells; ICIs, immune checkpoint inhibitors; IFN, interferon; LNP, lipid nanoparticle; PD-1, programmed cell death protein-1; PD-L1, programmed death-ligand 1; tdLN, tumor-draining lymph node; TME, tumor microenvironment.

mRNA-LNP-based vaccines are highly versatile and customizable, suggesting that they can be incorporated into the oncological armamentarium designed to improve ICI effects. To achieve the full potential of combinations between mRNA vaccines and ICIs, it will be important to further extend the mechanistic characterization pioneered by Grippin et al.¹ Recent studies unraveled that mRNA-LNP therapeutics interact with both innate and adaptive immune arms and reshape host immunity in a context-dependent manner, with IFN-I signaling occupying a central non-redundant role.³ For example, the COVID-19 mRNA vaccine-induced “trained immunity” involving innate immune cells,⁴ especially macrophages and natural killer cells, bears potential to affect the antitumor immune effectors. Of note, SARS-CoV-2 mRNA vaccination elicits histone H3 lysine 27 acetylation (H3K27ac) at promoters of innate immune genes in monocyte-derived macrophages, serving as an epigenetic memory mark that persists for several months. Importantly, a prime-boost vaccination regimen is required to achieve significant and durable epigenetic reprogramming that likely affects hematopoietic stem cells based on the observation that this innate immune memory outlasts the short lifespan of circulating monocytes.⁵ This vaccine-induced epigenetic remodeling broadens non-specific innate immune priming. Indeed, it enhances macrophage responsiveness to diverse pathogen-associated molecular patterns (PAMPs) beyond SARS-CoV-2, resulting in potent secretion of pro-inflammatory cytokines including interleukin (IL)-1β, tumor necrosis factor-α and IL-36 on restimulation.⁵ Similarly, PAMPs or danger-associated molecular patterns (DAMPs) and cytokines (especially IFN-I) induced by vaccinations can promote “maturation” and lymph node homing of DCs and aid presentation of otherwise inaccessible tumor antigens via “antigen spreading” from vaccine-damaged malignant cells.^{5 6} Vaccine-induced reprogramming of innate immunity ultimately enables “help” from CD4⁺ T cells for effective activation of cytotoxic antitumor CD8⁺ T cells.^{5 6} Additionally, T cells specific for microbial antigens can attack malignant cells due to “cross-reactivity” with TAAs.^{3 6 7} These mRNA vaccine-induced immunostimulatory effects subvert immunosuppression in TME, thus reactivating the cancer immunity cycle required for ICI-elicited antitumor CD8⁺ T cell response.

Early during the COVID-19 pandemic, in 2020, we advanced the hypothesize that the antiviral CD8⁺ T cell immunity against SARS-CoV-2 (induced via natural infections or vaccinations) might be harnessed for building a new immunotherapeutic avenue for oncological indications.⁸ This scientific perspective stemmed from the extensive evidence supporting the antitumor benefits of antiviral immunity induced by oncolytic viruses (OVs).⁹ US Food and Drug Administration-approved and experimental OVs are known for their capacity to preferentially infect and kill malignant cells are being tested in numerous clinical trials worldwide. OVs do not only cause cancer cell killing or “oncolysis”, but also mediate vast immunomodulatory effects, thus over-riding tumor-associated immune evasion mechanisms, promoting protective antitumor immunity, and enhancing the therapeutic efficacy of mainstream ICIs by rendering tumors “hot”. Recent work integrating oncolytic virotherapy with modern immunotherapy has emphasized that OV-driven IFN-I production, DAMP release, and enhanced antigen presentation are mechanistically analogous to those described for mRNA-LNP vaccines. The paper by Grippin et al¹ reports similar mechanisms.

Conclusions and future directions

It is worth noting that the foundations of modern cancer immunotherapy are rooted in clinical observations correlating antitumor benefits with immunity induced by natural infections. In the late 1890s, Dr William Coley, the father of cancer immunotherapy, discovered that local bacterial infections could halt the advancement of sarcomas in patients. Similarly, other microbes and microbe-based products (eg, BCG vaccine¹⁰ for bladder cancer treatment) can induce immunogenic cell death and promote antitumor immunity. Moreover, intravesical BCG triggers trained immunity, DAMP release and IFN-I-driven remodeling of the bladder tumor milieu. Intriguingly, incidental infections of patients by influenza, measles or hepatitis virus have been linked to improved cancer immunosurveillance. Thus, immunological mechanisms induced by microbial infections or vaccines hold untapped potential to prime host immunity against cancers.

mRNA vaccines against COVID-19 and other infections can potentiate ICI efficacy. As many of these vaccines are already approved or nearing clinical implementation, their repurposing for cancer immunotherapy is now a realistic translational opportunity. The broader lesson spanning Coley’s foundational observations and contemporary mRNA vaccination is therefore emphatically not that infections occasionally coincide with tumor regression. Rather, the field now recognizes that such phenomena are underpinned by an actionable set of immunological principles, including pattern-recognition receptor signaling, robust IFN-I induction, DC activation, trained innate immunity, antigen spreading, and the durable expansion of polyclonal antitumor T cell responses. In this light, cancer immunotherapy has unequivocally moved beyond anecdote and serendipity toward mechanism-based immune programming. What remains unresolved is not whether vaccine-induced or infection-induced inflammation can convert immunologically “cold” tumors into ICI-responsive lesions, but rather how, when, and in whom these inflammatory circuits can be predictably and safely engaged across diverse tumor types and host immunological states.

A central imperative for the field will require coherent and systemic integration of multi-omics analyses. For example, snapshot multi-omics analyses can define the molecular architecture of response and resistance by capturing tumor-cell states, stromal programs, myeloid activation, T cell dysfunction, IFN signaling, microbiome configurations, and the spatial organization of the TME. On the other hand, serial profiling based on structured patient medical histories can reveal the host immune context that determines whether vaccine-induced inflammation is beneficial, neutral, or deleterious. The integration of these multidimensional datasets with machine learning and artificial intelligence pipelines will guide future cancer immunotherapy paradigms that are both highly efficacious and broadly applicable across patient populations.

Looking ahead, the optimal harnessing of vaccine-augmented cancer immunotherapy will be enabled by prospective, mechanism-oriented studies integrating longitudinal profiling of the same patients before and after vaccination. Such an approach may help distinguish at least three clinically relevant scenarios: (1) tumors lacking TILs because immune priming never occurred, (2) tumors infiltrated by bystander, non-tumor-reactive lymphocytes, and (3) tumors containing tumor-reactive T cells that are present but functionally restrained. These distinctions matter because they are likely to require different interventions, including stronger innate priming and antigen presentation, induction of antigen spreading or cross-reactive recall responses, or release from suppressive checkpoints and metabolic constraints. Such an integrated framework may also clarify whether the antitumor effects of infectious disease vaccines are driven mainly by non-specific adjuvanticity, trained innate immunity, or cognate cross-reactive T cell recognition of tumor and microbial antigens. This point is central for clinical translation because each mechanism implies different biomarkers and treatment strategies. In conclusion, while the field has advanced markedly since Coley’s original observations, durable and widespread clinical implementation will ultimately depend on prospective mechanistic translational studies that precisely align vaccine-based immune priming strategies with tumor- and host-specific states of immune exclusion, dysfunction, or ignorance.²