The manuscript of Solari et al entitled “ Damage-associated molecular patterns (DAMPs) related to immunogenic cell death are differentially triggered by clinically relevant chemotherapeutics in lung adenocarcinoma cells” is a very interesting and important work showing that cisplatin acts as an immunogenic inducer with the expression of ICD hallmarks (CRT, ATP, HMGB1) and autophagy and apoptosis markers as well. The paper is well written and well understandable. However some major and minor points have to be improved in the manuscript before being published. Major revision is requested.

Major points: 1) The authors claim that no permeabilization step has been performed before calreticulin (CRT) measurement. However, cells have been fixed with PFA4%. PFA can permeabilize cell plasma membrane. I suggest to the authors to perform this experiment with alive cells kept on cold ice to be sure to measure ecto-CRT. 2) Timepoints to determine CRT exposure, apoptosis and autophagy are very late (48h). Timepoints usually used are between 6-8 hours. May the authors give an explanation on their choice of timepoints? 3) Concerning the Principal Component Analysis (PCA), it is important to show how the weights for each parameter were determined. The authors have to explain in the statistical analysis paragraph how they have achieved PCA. 4) Finally, it is mandatory to validate the index of immunogenicity with another drug library known in the literature composed of immunogenic and non-immunogenic drugs (NCI library for instance). 5) In the discussion the authors declare that autophagy is a premortem stress mandatory to ATP release. It may be an interesting data if the authors prove a correlation between autophagy and ATP release with their data. Moreover the use of autophagy inhibitors (such as mTOR) can confirm the role of autophagy in ATP release mechanism. 6) In the discussion the authors mention that Endoplasmic Reticulum (ER) stress is a previous premortem stress preceding CRT exposure. It has been demonstrated that Immunogenic Cell Death (ICD) is preceded by a split of ER stress with just the induction of eIF2alpha phosphorylation (PMID: 29358668). I advise the authors to investigate if their ICD drugs induce a split of ER stress. The three arms of ER stress have to be studied (PERK, IRE1, ATF6 and their downstream pathways). The authors can use biosensors (GFP-ATF4, GFP-ATF6, GFP-XBP1s cell lines), or perform some immunoblots to detect the active forms of ER stress proteins. In addition, it has been described that CRT exposure and autophagy were correlated with eIF2alpha phosphorylation. I suggest to the authors to look for this correlation with their data.

Minor points: 1) In the abstract (Result part), the word “IndImmunog” is mistyping. 2) Figure 4A and 4B: in the legend of y-axis: separate the words “to” and “control” 3) Page 9 column 1: In the title beginning by « Index of immunogenicity », the word « IndImmunog » is mistyping. 4) In the list of abbreviations: please write endoplasmic reticulum instead of reticulum endoplasmic 5) The authors have to specify in statistical analysis paragraph if each experiment has been done three times independently and if the results are expressed as the mean of these three experiments. Moreover, the authors have to indicate if each condition has been done in triplicate or in quadruplicate.