Vaccination influenz(a)ing cancer-specific survival.

Abstract

The development of cancer-specific vaccines has a long history, beginning with the use of bacteria or bacterial toxins by Wiliam Cooley with the rationale to stimulate the immune system and thereby enhance tumor cell killing, leading to the use of bacillus calmette-guérin (BCG) for superficial bladder cancer.1 This currently led to the most recent developments with the generation of cancer vaccines, such as highly innovative individualized RNA vaccines developed based on the tumor-specific mutational profile, that will hopefully enable the breakthrough of this long and often disappointing journey.2 These vaccines are often accompanied by the application of components of bacterial or viral adjuvants, known to trigger pattern recognition receptors (eg, TLRs, STING, RIGI) or by cytokines.3 Some of these compounds are already tested as cancer therapeutics, and it is tempting to speculate that infectious vaccines, which are accompanied by a systemic immune activation, may also impact cancer-specific survival. The group of Gögenur et al linked the timing of influenza-vaccination after curative surgery for cancer with clinical outcome (overall mortality and cancer-specific mortality) using one of the well-known nordic population-based registries (in this case the Danish one).4 They demonstrate in this issue of The International Journal of Cancer that from 21 462 patients undergoing curative surgical cancer resection, 2557 received an influenza vaccine within 6 months after surgery.4 In particular, in patients receiving the vaccine within 30 days after surgery, the authors demonstrate that influencing vaccination impacts all-cause as well as cancer-specific mortality in a significant manner (hazard ratio 0.89 and 0.82, respectively). The data are of high oncological interest, even though the mechanisms underlying this observation remain speculative and hypothesis-generating. Most importantly and based on the registry-based character of this study, it is unclear if there were differences in relapse-sensing, which means that vaccinated patients are more compliant with respect to their cancer surveillance. This may impact the stage at diagnosis, the following treatment schedules and thus the prognosis in case of relapse. However, given that the observation is caused by a biological mechanism, data from preclinical mouse models as well as cancer patients suggest that vaccines may impact postsurgical NK dysfunction.5 Perioperative administration of oncolytic parapoxvirus ovis and vaccinia virus reversed NK cell suppression, which correlates with a reduction in the postoperative metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, which could be increased by an oncolytic vaccinia virus. Moreover, systemic application of oncolytic viruses, such as VSV-GP (in addition to local applications) is an appropriate tool to use oncolytic virus therapies, as this has also been shown to been able to locally reprogram the cancer microenvironment.6 A more recent and very elegant study further highlights the potency of intratumor application of an unaltered influenza vaccine.7 This procedure converted immunologically inactive cold tumors to immune-infiltrated hot tumors by augmenting DCs (including cross-presenting DCs) and tumor antigen-specific CD8+ T cells within the tumor microenvironment in mice including humanized cancer models. Of note, in this model of intratumor application, the adjuvanted formulation was not able to boost antitumor immune responses as it rather boosts anti-infectious immunity and induced recruitment of IL-10 producing regulatory B cells to the tumor site. How the formulation of the trivalent vaccine used in the paper by Gögenur and colleagues in the classical intramuscular injection systemically boosts adaptive and/or innate immune responses in the complete remission setting after surgical resection of a cancer in curative intent remains to be shown in future functional studies. The observation that the effect of the vaccine is most pronounced early after surgery may point to a special permissive immunological environment early upon surgery, enabling the generation of an effective anticancer immune response, ultimately preventing disease relapse. This may be at least in part explained, for example, by a retraction of the Treg pool upon cancer load reduction,8 which would impair the systemic antitumor immunity. The authors declare no conflicts of interest.