The majority of lung cancer patients progressing from conventional therapies are refractory to PD ‐L1/ PD ‐1 blockade monotherapy. Here, we show that baseline systemic CD 4 immunity is a differential factor for clinical responses. Patients with functional systemic CD 4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD 4 T cells. In these patients, CD 4 T cells possessed significant proliferative capacities, low co‐expression of PD ‐1/ LAG ‐3 and were responsive to PD ‐1 blockade ex vivo and in vivo . In contrast, patients with dysfunctional systemic CD 4 immunity did not respond even though they had lung cancer‐specific T cells. Although proficient in cytokine production, CD 4 T cells in these patients proliferated very poorly, strongly co‐upregulated PD ‐1/ LAG ‐3, and were largely refractory to PD ‐1 monoblockade. CD 8 immunity only recovered in patients with functional CD 4 immunity. T‐cell proliferative dysfunctionality could be reverted by PD ‐1/ LAG ‐3 co‐blockade. Patients with functional CD 4 immunity and PD ‐L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD 4 immunity for efficacious PD ‐L1/ PD ‐1 blockade therapy.

Preoperative physical exercise protocols prior to cancer surgery increased in popularity over recent years; however, the beneficial effect of such protocols is not well established, with conflicting results reported. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effects of different modalities or combinations of preoperative exercise interventions and/or prehabilitation multicomponent training in patients with non-small-cell lung cancer (NSCLC) after surgery on the outcomes related to functional capacity, mental wellness and medical care. We searched in OVID Embase, Pubmed, Cochrane Library, CINAHL, Scopus, and Web of Science. Characteristics of studies and program results and outcome data were extracted. Changes between the intervention and control groups, from baseline to follow-up (standardized mean difference (SMD) or relative risk (RR) with 95% confidence interval (CI) for each intervention was pooled using weighted random-effects models). A total of 676 participants from 10 RCTs were included in the final analysis (aerobic training + inspiratory muscle training, n = 5; aerobic training + strength training + inspiratory muscle training, n = 2; aerobic training + strength training, n = 1; multicomponent training, n = 1; aerobic training alone, n = 1). The results showed intervention-induced improvement in walking endurance (SMD = 0.27; 95% CI, 0.11 to 0.44; I2 = 0.0%), peak exercise capacity (SMD = 0.78; 95% CI, 0.35 to 1.21; I2 = 76.7%), dyspnoea (SMD = −0.30; 95% CI, −0.51 to −0.10; I2 = 0.0%), risk of hospitalization (SMD = −0.58; 95% CI, −0.97 to −0.20; I2 = 70.7%), and postoperative pulmonary complications (relative risk (RR) = 0.50; 95% CI, 0.39 to 0.66; I2 = 0.0%). For the functional capacity and medical care parameters, preoperative combined aerobic, resistance, and inspiratory muscle training was shown to be effective if comprising one to four weeks, performing 1–3 sessions per week, with moderate intensity (50% for endurance capacity). Further studies with larger samples and higher methodological quality are needed to clarify the potential benefits of preoperative exercise training for patients with NSCLC.

Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; p = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; p = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28− CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD (p = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, p = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, p = 0.0126). A strong expansion of CD28− CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation.