Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma

Abstract

BackgroundThe survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for the treatment of squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization of chemoimmunotherapy in order to enhance the efficacy of immune checkpoint inhibitors (ICIs) in SQCLC remains to be explored.MethodsCell lines, syngeneic immunocompetent mouse models, and patients’ peripheral blood mononuclear cells were used in order to comprehensively explore how to enhance ectopic lymphoid-like structures (ELSs) and upregulate the therapeutic targets of anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering SQCLC more sensitive to ICIs. In addition, molecular mechanisms underlying optimization were characterized.ResultsLow-dose chemotherapy contributed to an enhanced antigen exposure via the phosphatidylinositol 3-kinase/Akt/transcription factor nuclear factor kappa B signaling pathway. Improved antigen uptake and presentation by activated dendritic cells (DCs) was observed, thus invoking specific T cell responses leading to systemic immune responses and immunological memory. In turn, enhanced antitumor ELSs and PD-1/PD-L1 expression was observed in vivo. Moreover, upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and effectively synergized with anti-PD-1/PD-L1 mAbs. A possible mechanism underlying this synergy is the increase of activated type I macrophages, DCs, and cytotoxic CD8+ T cells, as well as the maintenance of intestinal gut microbiota diversity and composition. In contrast, when combining routine MTD chemotherapy with ICIs, the effects appeared to be additive rather than synergistic.ConclusionsWe first attempted to optimize chemoimmunotherapy for SQCLC by investigating different combinatorial modes. Compared with the MTD chemotherapy used in current clinical practice, upfront metronomic chemotherapy performed better with subsequent anti-PD-1/PD-L1 mAb treatment. This combination approach is worth investigating in other types of tumors, followed by translation into the clinic in the future.

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“…Additionally, increased understanding of the tumor microenvironment has led to the coupling of immunomodulatory therapies with chemotherapy ("chemoimmunotherapy") for the treatment of different cancers [41][42][43]. For example, squamous cell lung carcinoma represents up to 30% of all non-small cell lung cancers, yet treatment options are limited and mostly ineffective [44]. Squamous cell lung carcinoma tumors are more resistant to immunotherapy, and traditional chemotherapy treatments administered at the maximum tolerated dose are highly toxic to the patient with little effect on the tumor [44].…”

“…For example, squamous cell lung carcinoma represents up to 30% of all non-small cell lung cancers, yet treatment options are limited and mostly ineffective [44]. Squamous cell lung carcinoma tumors are more resistant to immunotherapy, and traditional chemotherapy treatments administered at the maximum tolerated dose are highly toxic to the patient with little effect on the tumor [44]. However, recent clinical trials have shown that coupling traditional chemotherapy with immunomodulatory therapy significantly increased patient survival [44].…”

Intratumoural administration and tumour tissue targeting of cancer immunotherapies

“…Unsurprisingly, therefore, the median duration of tumour responses with such combinations are not very different from those observed with chemotherapy alone in all of the registration trials 249 , 250 . Indeed, data from longer-term follow-up studies of those trials 251 , preclinical data 252 and case reports 253 suggest that systemic high-dose chemotherapies have a detrimental effect on the efficacy of anti-PD-1 and anti-PD-L1 antibodies, thus supporting the idea that metronomic chemotherapy might be a better way to exploit these immunomodulatory effects.…”

Immunological impact of chemotherapy on the tumor microenvironment in gastric cancer

“…[10][11][12][13] Multiplex quantification of CD3 + and CD8 + T cells and flow cytometry analysis showed that PD-1 blockade favors tumor infiltration by CD8 + T cells, while in vivo CD8 + T cell depletion led to tumor growth restoration. 14,15 A previous report showed that chemotherapy could promote the differentiation of human T cells into Th1 and Th9 subtypes and cytotoxic T lymphocytes (CTLs) in vitro and in vivo. 16 As for TAMs, typically CD163-positive M2 macrophages, play an essential role in malignant tumor development, angiogenesis, lymphangiogenesis, and invasion as well as immune tolerance.…”

“…High densities of CD3 + and CD8 + T cells have been shown to be associated with prolonged survival and significant therapeutic responses in cancer patients 10–13 . Multiplex quantification of CD3 + and CD8 + T cells and flow cytometry analysis showed that PD‐1 blockade favors tumor infiltration by CD8 + T cells, while in vivo CD8 + T cell depletion led to tumor growth restoration 14,15 . A previous report showed that chemotherapy could promote the differentiation of human T cells into Th1 and Th9 subtypes and cytotoxic T lymphocytes (CTLs) in vitro and in vivo 16…”