A recent review suggested that chemotherapy may prime cancer to respond to checkpoint inhibition.1 According to the review, which was published in the Annals of Oncology earlier this year, this may occur for a variety of reasons, depending primarily on the mechanism of action of the chemotherapy in question. 

In the past, these predictions may have been surprising to researchers in oncology, as chemotherapy was previously thought to be immunosuppressive. Yet, the authors argue, the effects of chemotherapy can “induce favorable immunogenic conditions within the tumor microenvironment, which may be difficult to achieve by just targeting immune cells.” 

In this setting, chemotherapy functions as the first part of a 2-stage evolutionary trap, where in the first stage clinicians actively select for a tumor microenvironment in which checkpoint blockade is most likely to be effective. With cyclophosphamide, for example, immunogenic cell death may be induced, and the drug may lead to dendritic cell homeostasis.2,3 Both are favorable immunomodulatory effects that may lead to an improved immune response —especially, it appears, when checkpoint blockade is used. 

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A recent editorial published in the Annals of Oncology, however, suggests that the notion of turning “cold” tumors “hot” may be a misconception.4 This, according to a study author, Thomas Helleday, PhD, professor of translational oncology and director of the Sheffield Cancer Centre at the University of Sheffield, England, is for several key reasons, each of which has to do with the selective processes caused by chemotherapeutics. 

“Introducing mutations would occur only in a fraction of subclonal cells that replicate and survive from the treatment, of which there are very few, as most cells are also nonreplicative,” Dr Helleday said. “Those rare neoantigens would be insufficient for recognition of the whole tumor by the patient’s immune system.” Immunotherapy might, in this case, help to remove cells expressing these antigens — if they hadn’t already been destroyed by chemotherapy — but the rest of the tumor would likely continue to progress. 

According to Dr Helleday, mutations induced by chemotherapy will likely last for only a single generation, in contrast with the high, lasting mutation rates caused by a mismatch repair defect, another phenomenon linked to response to immunotherapy.

Dr Helleday does note, however, that improved checkpoint blockade response via the cGAS or STING pathways is possible, which can be triggered by chemotherapy. “Many chemotherapies are DNA damaging,” he said, noting that the cGAS pathway is linked to an improved immune response. “But this will not introduce neoantigens, so will not turn a ‘cold’ tumor ‘hot.’

“That doesn’t mean that combining the therapies is not a very good thing,” he added. “Patients not responding to immunooncology drugs may respond when chemotherapy is added, as outlined in the review by Dr Heinhuis and colleagues, but probably not because neoantigens are introduced by the chemotherapy.”

The authors of the review who highlight the potentially synergistic effects of chemotherapy and checkpoint inhibition note that more research is needed — and much of it is already ongoing — to determine the efficacy of a variety of possible combinations. Despite the reservations noted by Dr Helleday, the potential for synergistic effects of these medications appears promising.  

References 

  1. Heinhuis KM, Ros W, Kok M, Steeghs N, Beijnen JH, and Schellens JHM. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumorsAnn Oncol. 2019;30(2):219-235.
  2. Pol J, Vacchelli E, Aranda F, et al. Trial watch: immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology. 2015;4(4):e1008866.
  3. Schiavoni G, Sistigu A, Valentini M, et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 2011;71(3):768-778.
  4. Helleday T. Making immunotherapy ‘cold’ tumours ‘hot’ by chemotherapy-induced mutations—aa misconception ]. Ann Oncol. 2019;30(3):360-361.