Renata Andrea Rusu-Patraulea

Immunotherapy (IT) and especially immune checkpoint blockade (ICB) changed the therapeutic approach in non-small cell lung cancer (NSCLC). Nevertheless, primary or secondary resistance and a percentage of long responders and survivors have been observed. The aim of this study is to gain a deeper understanding of the complex mechanisms of primary and secondary resistance to IT, involving tumor cells, the tumor microenvironment (TME), and the host, in order to find strategies to overcome it. With this aim in mind, a search for key words has been performed to identify relevant evidence in the literature. The most widely used approach is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect on the enhancement of immunogenic cell death. Since a dual role has been observed, a lot of questions are yet to be answered regarding the complex effect of these therapies, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, and the optimal RT volumes, sites, and dose/fractionation regimens to favor immune stimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors on immune or tumor cells are under evaluation. The huge potential of combination therapies becoming apparent. Questions regarding targets, selection of patients, and time and sequence of administration are yet to be answered, considering the complex mechanisms of resistance. Dynamic biomarkers to guide personalized treatment decisions are needed.

Immunotherapy (IT) and especially immune checkpoint blockade (ICB) changed the therapeutic approaches in non-small cell lung cancer (NSCLC). Still, primary or second-ary resistance and a percentage of long responders and survivors have been observed. The objective is to have a deeper understanding of the complex mechanisms of primary and secondary resistance to IT involving tumor cells, TME and host, to find strategies to over-come it. In this aim a search of the key words has been performed to identify the relevant evidence in the literature. The most available approach thus far is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect in enhancement of immunogenic cell death. Even so, a lot of questions are to be answered, as a dual role has been observed, considering the complex effect, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, the optimal RT volumes, sites, dose/fractionation regimens, to favor immunostimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors, on immune or tumor cells, are under evalua-tion. In perspective, a huge potential of combination therapies is arising, but to which tar-get, to what patient, at what time and sequence to be administered, considering the complex mechanisms of resistance, needs dynamic biomarkers to guide the decisions, to-wards more personalized treatments.